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28 pages, 5774 KiB

Open AccessFeature PaperArticle

Rigorous Computational and Experimental Investigations on MDM2/MDMX-Targeted Linear and Macrocyclic Peptides

by David J. Diller, Jon Swanson, Alexander S. Bayden, Chris J. Brown, Dawn Thean, David P. Lane, Anthony W. Partridge, Tomi K. Sawyer and Joseph Audie

Molecules 2019, 24(24), 4586; https://doi.org/10.3390/molecules24244586 - 14 Dec 2019

Cited by 4 | Viewed by 3565

Abstract

There is interest in peptide drug design, especially for targeting intracellular protein–protein interactions. Therefore, the experimental validation of a computational platform for enabling peptide drug design is of interest. Here, we describe our peptide drug design platform (CMDInventus) and demonstrate its use in [...] Read more.

There is interest in peptide drug design, especially for targeting intracellular protein–protein interactions. Therefore, the experimental validation of a computational platform for enabling peptide drug design is of interest. Here, we describe our peptide drug design platform (CMDInventus) and demonstrate its use in modeling and predicting the structural and binding aspects of diverse peptides that interact with oncology targets MDM2/MDMX in comparison to both retrospective (pre-prediction) and prospective (post-prediction) data. In the retrospective study, CMDInventus modules (CMDpeptide, CMDboltzmann, CMDescore and CMDyscore) were used to accurately reproduce structural and binding data across multiple MDM2/MDMX data sets. In the prospective study, CMDescore, CMDyscore and CMDboltzmann were used to accurately predict binding affinities for an Ala-scan of the stapled α-helical peptide ATSP-7041. Remarkably, CMDboltzmann was used to accurately predict the results of a novel D-amino acid scan of ATSP-7041. Our investigations rigorously validate CMDInventus and support its utility for enabling peptide drug design. Full article

(This article belongs to the Special Issue Advances in Peptide and Peptidomimetic Design Inspiring Basic Science and Drug Discovery: A Themed Issue Honoring Professor Victor J. Hruby on the Occasion of His 80th Birthday)

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24 pages, 4559 KiB

Open AccessArticle

Structure–Activity Relationships of 7-Substituted Dimethyltyrosine-Tetrahydroisoquinoline Opioid Peptidomimetics

by Deanna Montgomery, Jessica P. Anand, Mason A. Baber, Jack J. Twarozynski, Joshua G. Hartman, Lennon J. Delong, John R. Traynor and Henry I. Mosberg

Molecules 2019, 24(23), 4302; https://doi.org/10.3390/molecules24234302 - 26 Nov 2019

Cited by 5 | Viewed by 3512

Abstract

The opioid receptors modulate a variety of biological functions, including pain, mood, and reward. As a result, opioid ligands are being explored as potential therapeutics for a variety of indications. Multifunctional opioid ligands, which act simultaneously at more than one type of opioid [...] Read more.

The opioid receptors modulate a variety of biological functions, including pain, mood, and reward. As a result, opioid ligands are being explored as potential therapeutics for a variety of indications. Multifunctional opioid ligands, which act simultaneously at more than one type of opioid receptor, show promise for use in the treatment of addiction, pain, and other conditions. Previously, we reported the creation of bifunctional kappa opioid receptor (KOR) agonist/mu opioid receptor (MOR) partial agonist ligands from the classically delta opioid receptor (DOR) antagonist selective dimethyltyrosine-tetrahydroisoquinoline (Dmt-Tiq) scaffold through the addition of a 7-benzyl pendant on the tetrahydroisoquinoline ring. This study further explores the structure–activity relationships surrounding 7-position pendants on the Dmt-Tiq scaffold. Some analogues maintain a KOR agonist/MOR partial agonist profile, which is being explored in the development of a treatment for cocaine addiction. Others display a MOR agonist/DOR antagonist profile, which has potential to be used in the creation of a less addictive pain medication. Ultimately, we report the synthesis and in vitro evaluation of novel opioid ligands with a variety of multifunctional profiles. Full article

(This article belongs to the Special Issue Advances in Peptide and Peptidomimetic Design Inspiring Basic Science and Drug Discovery: A Themed Issue Honoring Professor Victor J. Hruby on the Occasion of His 80th Birthday)

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17 pages, 2335 KiB

Open AccessArticle

Application of N-Dodecyl l-Peptide to Enhance Serum Stability while Maintaining Inhibitory Effects on Myometrial Contractions Ex Vivo

by Julien Poupart, Xin Hou, Sylvain Chemtob and William D. Lubell

Molecules 2019, 24(22), 4141; https://doi.org/10.3390/molecules24224141 - 15 Nov 2019

Cited by 2 | Viewed by 2560

Abstract

N-Alkylation and N-acylation of the prostaglandin-F_2α allosteric modulator l-PDC31 were performed to install various alkyl, PEG and isoprenoid groups onto the l-enantiomer of the peptide. Among the different bio-conjugates studied, the N-dodecyl analog reduced prostaglandin-F_2α-induced [...] Read more.

N-Alkylation and N-acylation of the prostaglandin-F_2α allosteric modulator l-PDC31 were performed to install various alkyl, PEG and isoprenoid groups onto the l-enantiomer of the peptide. Among the different bio-conjugates studied, the N-dodecyl analog reduced prostaglandin-F_2α-induced mouse myometrium contractions ex vivo. Furthermore, N-dodecyl-l-PDC31 exhibited improved stability in a mouse serum assay, likely due to protection from protease degradation by the lipid chain. Full article

(This article belongs to the Special Issue Advances in Peptide and Peptidomimetic Design Inspiring Basic Science and Drug Discovery: A Themed Issue Honoring Professor Victor J. Hruby on the Occasion of His 80th Birthday)

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10 pages, 2910 KiB

Open AccessArticle

Development of N-Acetylated Dipalmitoyl-S-Glyceryl Cysteine Analogs as Efficient TLR2/TLR6 Agonists

by Yang Zhou, Abid H. Banday, Victor J. Hruby and Minying Cai

Molecules 2019, 24(19), 3512; https://doi.org/10.3390/molecules24193512 - 27 Sep 2019

Cited by 6 | Viewed by 2839

Abstract

Cancer vaccine is a promising immunotherapeutic approach to train the immune system with vaccines to recognize and eliminate tumors. Adjuvants are compounds that are necessary in cancer vaccines to mimic an infection process and amplify immune responses. The Toll-like receptor 2 and 6 [...] Read more.

Cancer vaccine is a promising immunotherapeutic approach to train the immune system with vaccines to recognize and eliminate tumors. Adjuvants are compounds that are necessary in cancer vaccines to mimic an infection process and amplify immune responses. The Toll-like receptor 2 and 6 (TLR2/TLR6) agonist dipalmitoyl-S-glyceryl cysteine (Pam₂Cys) was demonstrated as an ideal candidate for synthetic vaccine adjuvants. However, the synthesis of Pam₂Cys requires expensive N-protected cysteine as a key reactant, which greatly limits its application as a synthetic vaccine adjuvant in large-scaled studies. Here, we report the development of N-acetylated Pam₂Cys analogs as TLR2/TLR6 agonists. Instead of N-protected cysteine, the synthesis utilizes N-acetylcysteine to bring down the synthetic costs. The N-acetylated Pam₂Cys analogs were demonstrated to activate TLR2/TLR6 in vitro. Moreover, molecular docking studies were performed to provide insights into the molecular mechanism of how N-acetylated Pam₂Cys analogs bind to TLR2/TLR6. Together, these results suggest N-acetylated Pam₂Cys analogs as inexpensive and promising synthetic vaccine adjuvants to accelerate the development of cancer vaccines in the future. Full article

(This article belongs to the Special Issue Advances in Peptide and Peptidomimetic Design Inspiring Basic Science and Drug Discovery: A Themed Issue Honoring Professor Victor J. Hruby on the Occasion of His 80th Birthday)

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12 pages, 4785 KiB

Open AccessArticle

Replacement of l-Amino Acids by d-Amino Acids in the Antimicrobial Peptide Ranalexin and Its Consequences for Antimicrobial Activity and Biodistribution

by Cornelius Domhan, Philipp Uhl, Christian Kleist, Stefan Zimmermann, Florian Umstätter, Karin Leotta, Walter Mier and Michael Wink

Molecules 2019, 24(16), 2987; https://doi.org/10.3390/molecules24162987 - 17 Aug 2019

Cited by 20 | Viewed by 3298

Abstract

Infections caused by multidrug-resistant bacteria are a global emerging problem. New antibiotics that rely on innovative modes of action are urgently needed. Ranalexin is a potent antimicrobial peptide (AMP) produced in the skin of the American bullfrog Rana catesbeiana. Despite strong antimicrobial [...] Read more.

Infections caused by multidrug-resistant bacteria are a global emerging problem. New antibiotics that rely on innovative modes of action are urgently needed. Ranalexin is a potent antimicrobial peptide (AMP) produced in the skin of the American bullfrog Rana catesbeiana. Despite strong antimicrobial activity against Gram-positive bacteria, ranalexin shows disadvantages such as poor pharmacokinetics. To tackle these problems, a ranalexin derivative consisting exclusively of d-amino acids (named danalexin) was synthesized and compared to the original ranalexin for its antimicrobial potential and its biodistribution properties in a rat model. Danalexin showed improved biodistribution with an extended retention in the organisms of Wistar rats when compared to ranalexin. While ranalexin is rapidly cleared from the body, danalexin is retained primarily in the kidneys. Remarkably, both peptides showed strong antimicrobial activity against Gram-positive bacteria and Gram-negative bacteria of the genus Acinetobacter with minimum inhibitory concentrations (MICs) between 4 and 16 mg/L (1.9–7.6 µM). Moreover, both peptides showed lower antimicrobial activities with MICs ≥32 mg/L (≥15.2 µM) against further Gram-negative bacteria. The preservation of antimicrobial activity proves that the configuration of the amino acids does not affect the anticipated mechanism of action, namely pore formation. Full article

(This article belongs to the Special Issue Advances in Peptide and Peptidomimetic Design Inspiring Basic Science and Drug Discovery: A Themed Issue Honoring Professor Victor J. Hruby on the Occasion of His 80th Birthday)

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17 pages, 2343 KiB

Open AccessArticle

A Structure—Activity Relationship Study of Bis-Benzamides as Inhibitors of Androgen Receptor—Coactivator Interaction

by Tae-Kyung Lee, Preethi Ravindranathan, Rajni Sonavane, Ganesh V. Raj and Jung-Mo Ahn

Molecules 2019, 24(15), 2783; https://doi.org/10.3390/molecules24152783 - 31 Jul 2019

Cited by 4 | Viewed by 3904

Abstract

The interaction between androgen receptor (AR) and coactivator proteins plays a critical role in AR-mediated prostate cancer (PCa) cell growth, thus its inhibition is emerging as a promising strategy for PCa treatment. To develop potent inhibitors of the AR–coactivator interaction, we have designed [...] Read more.

The interaction between androgen receptor (AR) and coactivator proteins plays a critical role in AR-mediated prostate cancer (PCa) cell growth, thus its inhibition is emerging as a promising strategy for PCa treatment. To develop potent inhibitors of the AR–coactivator interaction, we have designed and synthesized a series of bis-benzamides by modifying functional groups at the N/C-terminus and side chains. A structure–activity relationship study showed that the nitro group at the N-terminus of the bis-benzamide is essential for its biological activity while the C-terminus can have either a methyl ester or a primary carboxamide. Surveying the side chains with various alkyl groups led to the identification of a potent compound 14d that exhibited antiproliferative activity (IC₅₀ value of 16 nM) on PCa cells. In addition, biochemical studies showed that 14d exerts its anticancer activity by inhibiting the AR–PELP1 interaction and AR transactivation. Full article

(This article belongs to the Special Issue Advances in Peptide and Peptidomimetic Design Inspiring Basic Science and Drug Discovery: A Themed Issue Honoring Professor Victor J. Hruby on the Occasion of His 80th Birthday)

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14 pages, 1736 KiB

Open AccessArticle

LIR Motif-Containing Hyperdisulfide β-Ginkgotide is Cytoprotective, Adaptogenic, and Scaffold-Ready

by Bamaprasad Dutta, Jiayi Huang, Janet To and James P. Tam

Molecules 2019, 24(13), 2417; https://doi.org/10.3390/molecules24132417 - 30 Jun 2019

Cited by 5 | Viewed by 3958

Abstract

Grafting a bioactive peptide onto a disulfide-rich scaffold is a promising approach to improve its structure and metabolic stability. The ginkgo plant-derived β-ginkgotide β-gB1 is a highly unusual molecule: Small, hyperdisulfide, and found only in selected ancient plants. It also contains a conserved [...] Read more.

Grafting a bioactive peptide onto a disulfide-rich scaffold is a promising approach to improve its structure and metabolic stability. The ginkgo plant-derived β-ginkgotide β-gB1 is a highly unusual molecule: Small, hyperdisulfide, and found only in selected ancient plants. It also contains a conserved 16-amino-acid core with three interlocking disulfides, as well as a six-amino-acid inter-cysteine loop 2 suitable for grafting peptide epitopes. However, very little is known about this recently-discovered family of molecules. Here, we report the biophysical and functional characterizations of the β-ginkgotide β-gB1 from G. biloba. A circular dichroism spectroscopy analysis at 90 °C and proteolytic treatments of β-gB1 supported that it is hyperstable. Data mining revealed that the β-gB1 loop 2 contains the canonical LC3 interacting region (LIR) motif crucial for selective autophagy. Cell-based assays and pull-down experiments showed that β-gB1 is an adaptogen, able to maintain cellular homeostasis through induced autophagosomes formation and to protect cells by targeting intracellular proteins from stress-mediated damage against hypoxia and the hypoxia-reoxygenation of induced cell death. This is the first report of an LIR-containing peptide natural product. Together, our results suggest that the plant-derived β-ginkgotide is cytoprotective, capable of targeting intracellular proteins, and holds promise as a hyperdisulfide scaffold for engineering peptidyl therapeutics with enhanced structural and metabolic stability. Full article

(This article belongs to the Special Issue Advances in Peptide and Peptidomimetic Design Inspiring Basic Science and Drug Discovery: A Themed Issue Honoring Professor Victor J. Hruby on the Occasion of His 80th Birthday)

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21 pages, 2847 KiB

Open AccessArticle

Incorporation of Putative Helix-Breaking Amino Acids in the Design of Novel Stapled Peptides: Exploring Biophysical and Cellular Permeability Properties

by Anthony W. Partridge, Hung Yi Kristal Kaan, Yu-Chi Juang, Ahmad Sadruddin, Shuhui Lim, Christopher J. Brown, Simon Ng, Dawn Thean, Fernando Ferrer, Charles Johannes, Tsz Ying Yuen, Srinivasaraghavan Kannan, Pietro Aronica, Yaw Sing Tan, Mohan R. Pradhan, Chandra S. Verma, Jerome Hochman, Shiying Chen, Hui Wan, Sookhee Ha, Brad Sherborne, David P. Lane and Tomi K. Sawyer Show full author list Hide full author list

Molecules 2019, 24(12), 2292; https://doi.org/10.3390/molecules24122292 - 20 Jun 2019

Cited by 37 | Viewed by 7458

Abstract

Stapled α-helical peptides represent an emerging superclass of macrocyclic molecules with drug-like properties, including high-affinity target binding, protease resistance, and membrane permeability. As a model system for probing the chemical space available for optimizing these properties, we focused on dual Mdm2/MdmX antagonist stapled [...] Read more.

Stapled α-helical peptides represent an emerging superclass of macrocyclic molecules with drug-like properties, including high-affinity target binding, protease resistance, and membrane permeability. As a model system for probing the chemical space available for optimizing these properties, we focused on dual Mdm2/MdmX antagonist stapled peptides related to the p53 N-terminus. Specifically, we first generated a library of ATSP-7041 (Chang et al., 2013) analogs iteratively modified by L-Ala and D-amino acids. Single L-Ala substitutions beyond the Mdm2/(X) binding interfacial residues (i.e., Phe³, Trp⁷, and Cba¹⁰) had minimal effects on target binding, α-helical content, and cellular activity. Similar binding affinities and cellular activities were noted at non-interfacial positions when the template residues were substituted with their d-amino acid counterparts, despite the fact that d-amino acid residues typically ‘break’ right-handed α-helices. d-amino acid substitutions at the interfacial residues Phe³ and Cba¹⁰ resulted in the expected decreases in binding affinity and cellular activity. Surprisingly, substitution at the remaining interfacial position with its d-amino acid equivalent (i.e., Trp⁷ to d-Trp⁷) was fully tolerated, both in terms of its binding affinity and cellular activity. An X-ray structure of the d-Trp⁷-modified peptide was determined and revealed that the indole side chain was able to interact optimally with its Mdm2 binding site by a slight global re-orientation of the stapled peptide. To further investigate the comparative effects of d-amino acid substitutions we used linear analogs of ATSP-7041, where we replaced the stapling amino acids by Aib (i.e., R8⁴ to Aib⁴ and S5¹¹ to Aib¹¹) to retain the helix-inducing properties of α-methylation. The resultant analog sequence Ac–Leu–Thr–Phe–Aib–Glu–Tyr–Trp–Gln–Leu–Cba–Aib–Ser–Ala–Ala–NH₂ exhibited high-affinity target binding (Mdm2 K_d = 43 nM) and significant α-helicity in circular dichroism studies. Relative to this linear ATSP-7041 analog, several d-amino acid substitutions at Mdm2(X) non-binding residues (e.g., d-Glu⁵, d-Gln⁸, and d-Leu⁹) demonstrated decreased binding and α-helicity. Importantly, circular dichroism (CD) spectroscopy showed that although helicity was indeed disrupted by d-amino acids in linear versions of our template sequence, stapled molecules tolerated these residues well. Further studies on stapled peptides incorporating N-methylated amino acids, l-Pro, or Gly substitutions showed that despite some positional dependence, these helix-breaking residues were also generally tolerated in terms of secondary structure, binding affinity, and cellular activity. Overall, macrocyclization by hydrocarbon stapling appears to overcome the destabilization of α-helicity by helix breaking residues and, in the specific case of d-Trp⁷-modification, a highly potent ATSP-7041 analog (Mdm2 K_d = 30 nM; cellular EC₅₀ = 600 nM) was identified. Our findings provide incentive for future studies to expand the chemical diversity of macrocyclic α-helical peptides (e.g., d-amino acid modifications) to explore their biophysical properties and cellular permeability. Indeed, using the library of 50 peptides generated in this study, a good correlation between cellular permeability and lipophilicity was observed. Full article

(This article belongs to the Special Issue Advances in Peptide and Peptidomimetic Design Inspiring Basic Science and Drug Discovery: A Themed Issue Honoring Professor Victor J. Hruby on the Occasion of His 80th Birthday)

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23 pages, 1940 KiB

Open AccessArticle

Novel pH Selective, Highly Lytic Peptides Based on a Chimeric Influenza Hemagglutinin Peptide/Cell Penetrating Peptide Motif

by Bethany Algayer, Ann O’Brien, Aaron Momose, Dennis J. Murphy, William Procopio, David M. Tellers and Thomas J. Tucker

Molecules 2019, 24(11), 2079; https://doi.org/10.3390/molecules24112079 - 31 May 2019

Cited by 10 | Viewed by 4341

Abstract

Delivery of macromolecular cargos such as siRNA to the cytosol after endocytosis remains a critical challenge. Numerous approaches including viruses, lipid nanoparticles, polymeric constructs, and various peptide-based approaches have yet to yield a general solution to this delivery issue. In this manuscript, we [...] Read more.

Delivery of macromolecular cargos such as siRNA to the cytosol after endocytosis remains a critical challenge. Numerous approaches including viruses, lipid nanoparticles, polymeric constructs, and various peptide-based approaches have yet to yield a general solution to this delivery issue. In this manuscript, we describe our efforts to design novel endosomolytic peptides that could be used to facilitate the release of cargos from a late endosomal compartment. These amphiphilic peptides, based on a chimeric influenza hemagglutinin peptide/cell-penetrating peptide (CPP) template, utilize a pH-triggering mechanism in which the peptides are protonated after acidification of the endosome, and thereby adopt an alpha-helical conformation. The helical forms of the peptides are lytically active, while the non-protonated forms are much less or non-lytically active at physiological pH. Starting from an initial lead peptide (INF7-Tat), we systematically modified the sequence of the chimeric peptides to obtain peptides with greatly enhanced lytic activity that maintain good pH selectivity in a red blood cell hemolysis assay. Full article

(This article belongs to the Special Issue Advances in Peptide and Peptidomimetic Design Inspiring Basic Science and Drug Discovery: A Themed Issue Honoring Professor Victor J. Hruby on the Occasion of His 80th Birthday)

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28 pages, 3471 KiB

Open AccessArticle

ACPred: A Computational Tool for the Prediction and Analysis of Anticancer Peptides

by Nalini Schaduangrat, Chanin Nantasenamat, Virapong Prachayasittikul and Watshara Shoombuatong

Molecules 2019, 24(10), 1973; https://doi.org/10.3390/molecules24101973 - 22 May 2019

Cited by 146 | Viewed by 7638

Abstract

Anticancer peptides (ACPs) have emerged as a new class of therapeutic agent for cancer treatment due to their lower toxicity as well as greater efficacy, selectivity and specificity when compared to conventional small molecule drugs. However, the experimental identification of ACPs still remains [...] Read more.

Anticancer peptides (ACPs) have emerged as a new class of therapeutic agent for cancer treatment due to their lower toxicity as well as greater efficacy, selectivity and specificity when compared to conventional small molecule drugs. However, the experimental identification of ACPs still remains a time-consuming and expensive endeavor. Therefore, it is desirable to develop and improve upon existing computational models for predicting and characterizing ACPs. In this study, we present a bioinformatics tool called the ACPred, which is an interpretable tool for the prediction and characterization of the anticancer activities of peptides. ACPred was developed by utilizing powerful machine learning models (support vector machine and random forest) and various classes of peptide features. It was observed by a jackknife cross-validation test that ACPred can achieve an overall accuracy of 95.61% in identifying ACPs. In addition, analysis revealed the following distinguishing characteristics that ACPs possess: (i) hydrophobic residue enhances the cationic properties of α-helical ACPs resulting in better cell penetration; (ii) the amphipathic nature of the α-helical structure plays a crucial role in its mechanism of cytotoxicity; and (iii) the formation of disulfide bridges on β-sheets is vital for structural maintenance which correlates with its ability to kill cancer cells. Finally, for the convenience of experimental scientists, the ACPred web server was established and made freely available online. Full article

(This article belongs to the Special Issue Advances in Peptide and Peptidomimetic Design Inspiring Basic Science and Drug Discovery: A Themed Issue Honoring Professor Victor J. Hruby on the Occasion of His 80th Birthday)

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17 pages, 10237 KiB

Open AccessArticle

The Characteristics of PD-L1 Inhibitors, from Peptides to Small Molecules

by Yanwen Zhong, Xuanyi Li, Hequan Yao and Kejiang Lin

Molecules 2019, 24(10), 1940; https://doi.org/10.3390/molecules24101940 - 20 May 2019

Cited by 12 | Viewed by 4936

Abstract

The programmed cell death ligand protein 1 (PD-L1) is a member of the B7 protein family and consists of 290 amino acid residues. The blockade of the PD-1/PD-L1 immune checkpoint pathway is effective in tumor treatment. Results: Two pharmacophore models were generated based [...] Read more.

The programmed cell death ligand protein 1 (PD-L1) is a member of the B7 protein family and consists of 290 amino acid residues. The blockade of the PD-1/PD-L1 immune checkpoint pathway is effective in tumor treatment. Results: Two pharmacophore models were generated based on peptides and small molecules. Hypo 1A consists of one hydrogen bond donor, one hydrogen bond acceptor, two hydrophobic points and one aromatic ring point. Hypo 1B consists of one hydrogen bond donor, three hydrophobic points and one positive ionizable point. Conclusions: The pharmacophore model consisting of a hydrogen bond donor, hydrophobic points and a positive ionizable point may be helpful for designing small-molecule inhibitors targeting PD-L1. Full article

(This article belongs to the Special Issue Advances in Peptide and Peptidomimetic Design Inspiring Basic Science and Drug Discovery: A Themed Issue Honoring Professor Victor J. Hruby on the Occasion of His 80th Birthday)

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12 pages, 2027 KiB

Open AccessArticle

Aza-Amino Acids Disrupt β-Sheet Secondary Structures

by Michael A. McMechen, Evan L. Willis, Preston C. Gourville and Caroline Proulx

Molecules 2019, 24(10), 1919; https://doi.org/10.3390/molecules24101919 - 18 May 2019

Cited by 11 | Viewed by 5004

Abstract

Cα to N substitution in aza-amino acids imposes local conformational constraints, changes in hydrogen bonding properties, and leads to adaptive chirality at the nitrogen atom. These properties can be exploited in mimicry and stabilization of peptide secondary structures and self-assembly. Here, the effect [...] Read more.

Cα to N substitution in aza-amino acids imposes local conformational constraints, changes in hydrogen bonding properties, and leads to adaptive chirality at the nitrogen atom. These properties can be exploited in mimicry and stabilization of peptide secondary structures and self-assembly. Here, the effect of a single aza-amino acid incorporation located in the upper β-strand at a hydrogen-bonded (HB) site of a β-hairpin model peptide (H-Arg-Tyr-Val-Glu-Val-d-Pro-Gly-Orn-Lys-Ile-Leu-Gln-NH₂) is reported. Specifically, analogs in which valine³ was substituted for aza-valine³ or aza-glycine³ were synthesized, and their β-hairpin stabilities were examined using Nuclear Magnetic Resonance (NMR) spectroscopy. The azapeptide analogs were found to destabilize β-hairpin formation compared to the parent peptide. The aza-valine³ residue was more disruptive of β-hairpin geometry than its aza-glycine³ counterpart. Full article

(This article belongs to the Special Issue Advances in Peptide and Peptidomimetic Design Inspiring Basic Science and Drug Discovery: A Themed Issue Honoring Professor Victor J. Hruby on the Occasion of His 80th Birthday)

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15 pages, 3826 KiB

Open AccessArticle

Rapid Discovery of Illuminating Peptides for Instant Detection of Opioids in Blood and Body Fluids

by Shabnam Jafari, Yann Thillier, Yousif H. Ajena, Diedra Shorty, Jiannan Li, Jonathan S. Huynh, Bethany Ming-Choi Pan, Tingrui Pan, Kit S. Lam and Ruiwu Liu

Molecules 2019, 24(9), 1813; https://doi.org/10.3390/molecules24091813 - 10 May 2019

Cited by 4 | Viewed by 4726

Abstract

The United States is currently experiencing an opioid crisis, with more than 47,000 deaths in 2017 due to opioid overdoses. Current approaches for opioid identification and quantification in body fluids include immunoassays and chromatographic methods (e.g., LC-MS, GC-MS), which require expensive instrumentation and [...] Read more.

The United States is currently experiencing an opioid crisis, with more than 47,000 deaths in 2017 due to opioid overdoses. Current approaches for opioid identification and quantification in body fluids include immunoassays and chromatographic methods (e.g., LC-MS, GC-MS), which require expensive instrumentation and extensive sample preparation. Our aim was to develop a portable point-of-care device that can be used for the instant detection of opioids in body fluids. Here, we reported the development of a morphine-sensitive fluorescence-based sensor chip to sensitively detect morphine in the blood using a homogeneous immunoassay without any washing steps. Morphine-sensitive illuminating peptides were identified using a high throughput one-bead one-compound (OBOC) combinatorial peptide library approach. The OBOC libraries contain a large number of random peptides with a molecular rotor dye, malachite green (MG), that are coupled to the amino group on the side chain of lysine at different positions of the peptides. The OBOC libraries were then screened for fluorescent activation under a confocal microscope, using an anti-morphine monoclonal antibody as the screening probe, in the presence and absence of free morphine. Using this novel three-step fluorescent screening assay, we were able to identify the peptide-beads that fluoresce in the presence of an anti-morphine antibody, but lost fluorescence when the free morphine was present. After the positive beads were decoded using automatic Edman microsequencing, the morphine-sensitive illuminating peptides were then synthesized in soluble form, functionalized with an azido group, and immobilized onto microfabricated PEG-array spots on a glass slide. The sensor chip was then evaluated for the detection of morphine in plasma. We demonstrated that this proof-of-concept platform can be used to develop fluorescence-based sensors against morphine. More importantly, this technology can also be applied to the discovery of other novel illuminating peptidic sensors for the detection of illicit drugs and cancer biomarkers in body fluids. Full article

(This article belongs to the Special Issue Advances in Peptide and Peptidomimetic Design Inspiring Basic Science and Drug Discovery: A Themed Issue Honoring Professor Victor J. Hruby on the Occasion of His 80th Birthday)

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19 pages, 3542 KiB

Open AccessFeature PaperArticle

Triazolopeptides Inhibiting the Interaction between Neuropilin-1 and Vascular Endothelial Growth Factor-165

by Bartlomiej Fedorczyk, Piotr F. J. Lipiński, Anna K. Puszko, Dagmara Tymecka, Beata Wilenska, Wioleta Dudka, Gerard Y. Perret, Rafal Wieczorek and Aleksandra Misicka

Molecules 2019, 24(9), 1756; https://doi.org/10.3390/molecules24091756 - 6 May 2019

Cited by 14 | Viewed by 4093

Abstract

Inhibiting the interaction of neuropilin-1 (NRP-1) with vascular endothelial growth factor (VEGF) has become an interesting mechanism for potential anticancer therapies. In our previous works, we have obtained several submicromolar inhibitors of this interaction, including branched pentapeptides of general structure Lys(Har)-Xxx-Xxx-Arg. With the [...] Read more.

Inhibiting the interaction of neuropilin-1 (NRP-1) with vascular endothelial growth factor (VEGF) has become an interesting mechanism for potential anticancer therapies. In our previous works, we have obtained several submicromolar inhibitors of this interaction, including branched pentapeptides of general structure Lys(Har)-Xxx-Xxx-Arg. With the intent to improve the proteolytic stability of our inhibitors, we turned our attention to 1,4-disubstituted 1,2,3-triazoles as peptide bond isosteres. In the present contribution, we report the synthesis of 23 novel triazolopeptides along with their inhibitory activity. The compounds were synthesized using typical peptide chemistry methods, but with a conversion of amine into azide completely on solid support. The inhibitory activity of the synthesized derivatives spans from 9.2% to 58.1% at 10 μM concentration (the best compound Lys(Har)-GlyΨ[Trl]GlyΨ[Trl]Arg, 3, IC₅₀ = 8.39 μM). Synthesized peptidotriazoles were tested for stability in human plasma and showed remarkable resistance toward proteolysis, with half-life times far exceeding 48 h. In vitro cell survival test resulted in no significant impact on bone marrow derived murine cells 32D viability. By means of molecular dynamics, we were able to propose a binding mode for compound 3 and discuss the observed structure–activity relationships. Full article

(This article belongs to the Special Issue Advances in Peptide and Peptidomimetic Design Inspiring Basic Science and Drug Discovery: A Themed Issue Honoring Professor Victor J. Hruby on the Occasion of His 80th Birthday)

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35 pages, 10959 KiB

Open AccessArticle

Small AntiMicrobial Peptide with In Vivo Activity Against Sepsis

by Héloise Boullet, Fayçal Bentot, Arnaud Hequet, Carine Ganem-Elbaz, Chérine Bechara, Emeline Pacreau, Pierre Launay, Sandrine Sagan, Claude Jolivalt, Claire Lacombe, Roba Moumné and Philippe Karoyan

Molecules 2019, 24(9), 1702; https://doi.org/10.3390/molecules24091702 - 1 May 2019

Cited by 14 | Viewed by 4709

Abstract

Antimicrobial peptides (AMPs) are considered as potential therapeutic sources of future antibiotics because of their broad-spectrum activities and alternative mechanisms of action compared to conventional antibiotics. Although AMPs present considerable advantages over conventional antibiotics, their clinical and commercial development still have some limitations, [...] Read more.

Antimicrobial peptides (AMPs) are considered as potential therapeutic sources of future antibiotics because of their broad-spectrum activities and alternative mechanisms of action compared to conventional antibiotics. Although AMPs present considerable advantages over conventional antibiotics, their clinical and commercial development still have some limitations, because of their potential toxicity, susceptibility to proteases, and high cost of production. To overcome these drawbacks, the use of peptides mimics is anticipated to avoid the proteolysis, while the identification of minimalist peptide sequences retaining antimicrobial activities could bring a solution for the cost issue. We describe here new polycationic -amino acids combining these two properties, that we used to design small dipeptides that appeared to be active against Gram-positive and Gram-negative bacteria, selective against prokaryotic versus mammalian cells, and highly stable in human plasma. Moreover, the in vivo data activity obtained in septic mice reveals that the bacterial killing effect allows the control of the infection and increases the survival rate of cecal ligature and puncture (CLP)-treated mice. Full article

(This article belongs to the Special Issue Advances in Peptide and Peptidomimetic Design Inspiring Basic Science and Drug Discovery: A Themed Issue Honoring Professor Victor J. Hruby on the Occasion of His 80th Birthday)

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13 pages, 2961 KiB

Open AccessArticle

A Stapled Peptide Mimic of the Pseudosubstrate Inhibitor PKI Inhibits Protein Kinase A

by Jascha T. Manschwetus, George N. Bendzunas, Ameya J. Limaye, Matthias J. Knape, Friedrich W. Herberg and Eileen J. Kennedy

Molecules 2019, 24(8), 1567; https://doi.org/10.3390/molecules24081567 - 20 Apr 2019

Cited by 11 | Viewed by 5175

Abstract

Kinases regulate multiple and diverse signaling pathways and misregulation is implicated in a multitude of diseases. Although significant efforts have been put forth to develop kinase-specific inhibitors, specificity remains a challenge. As an alternative to catalytic inhibition, allosteric inhibitors can target areas on [...] Read more.

Kinases regulate multiple and diverse signaling pathways and misregulation is implicated in a multitude of diseases. Although significant efforts have been put forth to develop kinase-specific inhibitors, specificity remains a challenge. As an alternative to catalytic inhibition, allosteric inhibitors can target areas on the surface of an enzyme, thereby providing additional target diversity. Using cAMP-dependent protein kinase A (PKA) as a model system, we sought to develop a hydrocarbon-stapled peptide targeting the pseudosubstrate domain of the kinase. A library of peptides was designed from a Protein Kinase Inhibitor (PKI), a naturally encoded protein that serves as a pseudosubstrate inhibitor for PKA. The binding properties of these peptide analogs were characterized by fluorescence polarization and surface plasmon resonance, and two compounds were identified with K_D values in the 500–600 pM range. In kinase activity assays, both compounds demonstrated inhibition with 25–35 nM IC₅₀ values. They were also found to permeate cells and localize within the cytoplasm and inhibited PKA activity within the cellular environment. To the best of our knowledge, these stapled peptide inhibitors represent some of the highest affinity binders reported to date for hydrocarbon stapled peptides. Full article

(This article belongs to the Special Issue Advances in Peptide and Peptidomimetic Design Inspiring Basic Science and Drug Discovery: A Themed Issue Honoring Professor Victor J. Hruby on the Occasion of His 80th Birthday)

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15 pages, 2291 KiB

Open AccessArticle

Development of Highly Selective 1,2,3-Triazole-containing Peptidic Polo-like Kinase 1 Polo-box Domain-binding Inhibitors

by Xue Zhi Zhao, Kohei Tsuji, David Hymel and Terrence R. Burke, Jr.

Molecules 2019, 24(8), 1488; https://doi.org/10.3390/molecules24081488 - 16 Apr 2019

Cited by 6 | Viewed by 3933

Abstract

Members of the polo-like kinase (Plk) family of serine/threonine protein kinases play crucial roles in cell cycle regulation and proliferation. Of the five Plks (Plk1–5), Plk1 is recognized as an anticancer drug target. Plk1 contains multiple structural components that are important for its [...] Read more.

Members of the polo-like kinase (Plk) family of serine/threonine protein kinases play crucial roles in cell cycle regulation and proliferation. Of the five Plks (Plk1–5), Plk1 is recognized as an anticancer drug target. Plk1 contains multiple structural components that are important for its proper biological function. These include an N-terminal catalytic domain and a C-terminal non-catalytic polo-box domain (PBD). The PBD binds to phosphothreonine (pT) and phosphoserine-containing sequences. Blocking PBD-dependent interactions offers a potential means of down-regulating Plk1 function that is distinct from targeting its ATP-binding site. Previously, we demonstrated by tethering alkylphenyl chains from the N(π)-position of the His residue in the 5-mer PLHSpT, that we were able to access a hydrophobic “cryptic” binding pocket on the surface of the PBD, and in so doing enhance binding affinities by approximately 1000-fold. More recently, we optimized these PBD-ligand interactions using an oxime ligation-based strategy. Herein, using azide-alkyne cycloaddition reactions, we explore new triazole-containing PBD-binding antagonists. Some of these ligands retain the high PBD-binding affinity of the parent peptide, while showing desirable enhanced selectivity for the PBD of Plk1 relative to the PBDs of Plk2 and Plk3. Full article

(This article belongs to the Special Issue Advances in Peptide and Peptidomimetic Design Inspiring Basic Science and Drug Discovery: A Themed Issue Honoring Professor Victor J. Hruby on the Occasion of His 80th Birthday)

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13 pages, 1459 KiB

Open AccessArticle

Structure–Activity Relationships of the Tetrapeptide Ac-His-Arg-(pI)DPhe-Tic-NH₂ at the Mouse Melanocortin Receptors: Modification at the (pI)DPhe Position Leads to mMC3R Versus mMC4R Selective Ligands

by Katherine N. Schlasner, Mark D. Ericson, Skye R. Doering, Katie T. Freeman, Mary Weinrich and Carrie Haskell-Luevano

Molecules 2019, 24(8), 1463; https://doi.org/10.3390/molecules24081463 - 13 Apr 2019

Cited by 5 | Viewed by 3245

Abstract

The five melanocortin receptors (MC1R–MC5R) are involved in numerous biological pathways, including steroidogenesis, pigmentation, and food intake. In particular, MC3R and MC4R knockout mice suggest that the MC3R and MC4R regulate energy homeostasis in a non-redundant manner. While MC4R-selective agonists have been utilized [...] Read more.

The five melanocortin receptors (MC1R–MC5R) are involved in numerous biological pathways, including steroidogenesis, pigmentation, and food intake. In particular, MC3R and MC4R knockout mice suggest that the MC3R and MC4R regulate energy homeostasis in a non-redundant manner. While MC4R-selective agonists have been utilized as appetite modulating agents, the lack of MC3R-selective agonists has impeded progress in modulating this receptor in vivo. In this study, the (pI)DPhe position of the tetrapeptide Ac-His-Arg-(pI)DPhe-Tic-NH₂ (an MC3R agonist/MC4R antagonist ligand) was investigated with a library of 12 compounds. The compounds in this library were found to have higher agonist efficacy and potency at the mouse (m) MC3R compared to the MC4R, indicating that the Arg-DPhe motif preferentially activates the mMC3R over the mMC4R. This observation may be used in the design of new MC3R-selective ligands, leading to novel probe and therapeutic lead compounds that will be useful for treating metabolic disorders. Full article

(This article belongs to the Special Issue Advances in Peptide and Peptidomimetic Design Inspiring Basic Science and Drug Discovery: A Themed Issue Honoring Professor Victor J. Hruby on the Occasion of His 80th Birthday)

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Review

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14 pages, 1693 KiB

Open AccessFeature PaperReview

Current Mechanistic and Pharmacodynamic Understanding of Melanocortin-4 Receptor Activation

by Shubh Sharma, Alastair S. Garfield, Bhavik Shah, Patrick Kleyn, Ilia Ichetovkin, Ida Hatoum Moeller, William R. Mowrey and Lex H.T. Van der Ploeg

Molecules 2019, 24(10), 1892; https://doi.org/10.3390/molecules24101892 - 16 May 2019

Cited by 36 | Viewed by 5701

Abstract

In this work we summarize our understanding of melanocortin 4 receptor (MC4R) pathway activation, aiming to define a safe and effective therapeutic targeting strategy for the MC4R. Delineation of cellular MC4R pathways has provided evidence for distinct MC4R signaling events characterized by unique [...] Read more.

In this work we summarize our understanding of melanocortin 4 receptor (MC4R) pathway activation, aiming to define a safe and effective therapeutic targeting strategy for the MC4R. Delineation of cellular MC4R pathways has provided evidence for distinct MC4R signaling events characterized by unique receptor activation kinetics. While these studies remain narrow in scope, and have largely been explored with peptidic agonists, the results provide a possible correlation between distinct ligand groups and differential MC4R activation kinetics. In addition, when a set of small-molecule and peptide MC4R agonists are compared, evidence of biased signaling has been reported. The results of such mechanistic studies are discussed. Full article

(This article belongs to the Special Issue Advances in Peptide and Peptidomimetic Design Inspiring Basic Science and Drug Discovery: A Themed Issue Honoring Professor Victor J. Hruby on the Occasion of His 80th Birthday)

34 pages, 3755 KiB

Open AccessReview

Peptide Conjugates with Small Molecules Designed to Enhance Efficacy and Safety

by Rongjun He, Brian Finan, John P. Mayer and Richard D. DiMarchi

Molecules 2019, 24(10), 1855; https://doi.org/10.3390/molecules24101855 - 14 May 2019

Cited by 82 | Viewed by 13399

Abstract

Peptides constitute molecular diversity with unique molecular mechanisms of action that are proven indispensable in the management of many human diseases, but of only a mere fraction relative to more traditional small molecule-based medicines. The integration of these two therapeutic modalities offers the [...] Read more.

Peptides constitute molecular diversity with unique molecular mechanisms of action that are proven indispensable in the management of many human diseases, but of only a mere fraction relative to more traditional small molecule-based medicines. The integration of these two therapeutic modalities offers the potential to enhance and broaden pharmacology while minimizing dose-dependent toxicology. This review summarizes numerous advances in drug design, synthesis and development that provide direction for next-generation research endeavors in this field. Medicinal studies in this area have largely focused upon the application of peptides to selectively enhance small molecule cytotoxicity to more effectively treat multiple oncologic diseases. To a lesser and steadily emerging extent peptides are being therapeutically employed to complement and diversify the pharmacology of small molecule drugs in diseases other than just cancer. No matter the disease, the purpose of the molecular integration remains constant and it is to achieve superior therapeutic outcomes with diminished adverse effects. We review linker technology and conjugation chemistries that have enabled integrated and targeted pharmacology with controlled release. Finally, we offer our perspective on opportunities and obstacles in the field. Full article

(This article belongs to the Special Issue Advances in Peptide and Peptidomimetic Design Inspiring Basic Science and Drug Discovery: A Themed Issue Honoring Professor Victor J. Hruby on the Occasion of His 80th Birthday)

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