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23 pages, 8420 KiB

Open AccessArticle

Computational Design of Macrocyclic Binders of S100B(ββ): Novel Peptide Theranostics

by Srinivasaraghavan Kannan, Pietro G. A. Aronica, Thanh Binh Nguyen, Jianguo Li and Chandra S. Verma

Molecules 2021, 26(3), 721; https://doi.org/10.3390/molecules26030721 - 30 Jan 2021

Cited by 4 | Viewed by 3273

Abstract

S100B(ββ) proteins are a family of multifunctional proteins that are present in several tissues and regulate a wide variety of cellular processes. Their altered expression levels have been associated with several human diseases, such as cancer, inflammatory disorders and neurodegenerative conditions, and hence [...] Read more.

S100B(ββ) proteins are a family of multifunctional proteins that are present in several tissues and regulate a wide variety of cellular processes. Their altered expression levels have been associated with several human diseases, such as cancer, inflammatory disorders and neurodegenerative conditions, and hence are of interest as a therapeutic target and a biomarker. Small molecule inhibitors of S100B(ββ) have achieved limited success. Guided by the wealth of available experimental structures of S100B(ββ) in complex with diverse peptides from various protein interacting partners, we combine comparative structural analysis and molecular dynamics simulations to design a series of peptides and their analogues (stapled) as S100B(ββ) binders. The stapled peptides were subject to in silico mutagenesis experiments, resulting in optimized analogues that are predicted to bind to S100B(ββ) with high affinity, and were also modified with imaging agents to serve as diagnostic tools. These stapled peptides can serve as theranostics, which can be used to not only diagnose the levels of S100B(ββ) but also to disrupt the interactions of S100B(ββ) with partner proteins which drive disease progression, thus serving as novel therapeutics. Full article

(This article belongs to the Special Issue Implication of S100 Proteins in Inflammation and Cancer: S100 Proteins as Potential Pharmacological Targets)

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9 pages, 2016 KiB

Open AccessArticle

Targeting S100B with Peptides Encoding Intrinsic Aggregation-Prone Sequence Segments

by Joana S. Cristóvão, Mariana A. Romão, Rodrigo Gallardo, Joost Schymkowitz, Frederic Rousseau and Cláudio M. Gomes

Molecules 2021, 26(2), 440; https://doi.org/10.3390/molecules26020440 - 15 Jan 2021

Cited by 6 | Viewed by 2653

Abstract

S100 proteins assume a diversity of oligomeric states including large order self-assemblies, with an impact on protein structure and function. Previous work has uncovered that S100 proteins, including S100B, are prone to undergo β-aggregation under destabilizing conditions. This propensity is encoded in aggregation-prone [...] Read more.

S100 proteins assume a diversity of oligomeric states including large order self-assemblies, with an impact on protein structure and function. Previous work has uncovered that S100 proteins, including S100B, are prone to undergo β-aggregation under destabilizing conditions. This propensity is encoded in aggregation-prone regions (APR) mainly located in segments at the homodimer interface, and which are therefore mostly shielded from the solvent and from deleterious interactions, under native conditions. As in other systems, this characteristic may be used to develop peptides with pharmacological potential that selectively induce the aggregation of S100B through homotypic interactions with its APRs, resulting in functional inhibition through a loss of function. Here we report initial studies towards this goal. We applied the TANGO algorithm to identify specific APR segments in S100B helix IV and used this information to design and synthesize S100B-derived APR peptides. We then combined fluorescence spectroscopy, transmission electron microscopy, biolayer interferometry, and aggregation kinetics and determined that the synthetic peptides have strong aggregation propensity, interact with S100B, and may promote co-aggregation reactions. In this framework, we discuss the considerable potential of such APR-derived peptides to act pharmacologically over S100B in numerous physiological and pathological conditions, for instance as modifiers of the S100B interactome or as promoters of S100B inactivation by selective aggregation. Full article

(This article belongs to the Special Issue Implication of S100 Proteins in Inflammation and Cancer: S100 Proteins as Potential Pharmacological Targets)

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11 pages, 1148 KiB

Open AccessArticle

Tissue mRNA for S100A4, S100A6, S100A8, S100A9, S100A11 and S100P Proteins in Colorectal Neoplasia: A Pilot Study

by Eva Peterova, Jan Bures, Paula Moravkova and Darina Kohoutova

Molecules 2021, 26(2), 402; https://doi.org/10.3390/molecules26020402 - 14 Jan 2021

Cited by 5 | Viewed by 2796

Abstract

S100 proteins are involved in the pathogenesis of sporadic colorectal carcinoma through different mechanisms. The aim of our study was to assess tissue mRNA encoding S100 proteins in patients with non-advanced and advanced colorectal adenoma. Mucosal biopsies were taken from the caecum, transverse [...] Read more.

S100 proteins are involved in the pathogenesis of sporadic colorectal carcinoma through different mechanisms. The aim of our study was to assess tissue mRNA encoding S100 proteins in patients with non-advanced and advanced colorectal adenoma. Mucosal biopsies were taken from the caecum, transverse colon and rectum during diagnostic and/or therapeutic colonoscopy. Another biopsy was obtained from adenomatous tissue in the advanced adenoma group. The tissue mRNA for each S100 protein (S100A4, S100A6, S100A8, S100A9, S100A11 and S100P) was investigated. Eighteen biopsies were obtained from the healthy mucosa in controls and the non-advanced adenoma group (six individuals in each group) and thirty biopsies in the advanced adenoma group (ten patients). Nine biopsies were obtained from advanced adenoma tissue (9/10 patients). Significant differences in mRNA investigated in the healthy mucosa were identified between (1) controls and the advanced adenoma group for S100A6 (p = 0.012), (2) controls and the non-advanced adenoma group for S100A8 (p = 0.033) and (3) controls and the advanced adenoma group for S100A11 (p = 0.005). In the advanced adenoma group, differences between the healthy mucosa and adenomatous tissue were found in S100A6 (p = 0.002), S100A8 (p = 0.002), S100A9 (p = 0.021) and S100A11 (p = 0.029). Abnormal mRNA expression for different S100 proteins was identified in the pathological adenomatous tissue as well as in the morphologically normal large intestinal mucosa. Full article

(This article belongs to the Special Issue Implication of S100 Proteins in Inflammation and Cancer: S100 Proteins as Potential Pharmacological Targets)

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21 pages, 8304 KiB

Open AccessArticle

Specificity of Molecular Fragments Binding to S100B versus S100A1 as Identified by NMR and Site Identification by Ligand Competitive Saturation (SILCS)

by Brianna D. Young, Wenbo Yu, Darex J. Vera Rodríguez, Kristen M. Varney, Alexander D. MacKerell, Jr. and David J. Weber

Molecules 2021, 26(2), 381; https://doi.org/10.3390/molecules26020381 - 13 Jan 2021

Cited by 7 | Viewed by 3904

Abstract

S100B, a biomarker of malignant melanoma, interacts with the p53 protein and diminishes its tumor suppressor function, which makes this S100 family member a promising therapeutic target for treating malignant melanoma. However, it is a challenge to design inhibitors that are specific for [...] Read more.

S100B, a biomarker of malignant melanoma, interacts with the p53 protein and diminishes its tumor suppressor function, which makes this S100 family member a promising therapeutic target for treating malignant melanoma. However, it is a challenge to design inhibitors that are specific for S100B in melanoma versus other S100-family members that are important for normal cellular activities. For example, S100A1 is most similar in sequence and structure to S100B, and this S100 protein is important for normal skeletal and cardiac muscle function. Therefore, a combination of NMR and computer aided drug design (CADD) was used to initiate the design of specific S100B inhibitors. Fragment-based screening by NMR, also termed “SAR by NMR,” is a well-established method, and was used to examine spectral perturbations in 2D [¹H, ¹⁵N]-HSQC spectra of Ca²⁺-bound S100B and Ca²⁺-bound S100A1, side-by-side, and under identical conditions for comparison. Of the 1000 compounds screened, two were found to be specific for binding Ca²⁺-bound S100A1 and four were found to be specific for Ca²⁺-bound S100B, respectively. The NMR spectral perturbations observed in these six data sets were then used to model how each of these small molecule fragments showed specificity for one S100 versus the other using a CADD approach termed Site Identification by Ligand Competitive Saturation (SILCS). In summary, the combination of NMR and computational approaches provided insight into how S100A1 versus S100B bind small molecules specifically, which will enable improved drug design efforts to inhibit elevated S100B in melanoma. Such a fragment-based approach can be used generally to initiate the design of specific inhibitors for other highly homologous drug targets. Full article

(This article belongs to the Special Issue Implication of S100 Proteins in Inflammation and Cancer: S100 Proteins as Potential Pharmacological Targets)

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11 pages, 1231 KiB

Open AccessArticle

Calcium-Dependent Translocation of S100B Is Facilitated by Neurocalcin Delta

by Jingyi Zhang, Anuradha Krishnan, Hao Wu and Venkat Venkataraman

Molecules 2021, 26(1), 227; https://doi.org/10.3390/molecules26010227 - 5 Jan 2021

Cited by 3 | Viewed by 3733

Abstract

S100B is a calcium-binding protein that governs calcium-mediated responses in a variety of cells—especially neuronal and glial cells. It is also extensively investigated as a potential biomarker for several disease conditions, especially neurodegenerative ones. In order to establish S100B as a viable pharmaceutical [...] Read more.

S100B is a calcium-binding protein that governs calcium-mediated responses in a variety of cells—especially neuronal and glial cells. It is also extensively investigated as a potential biomarker for several disease conditions, especially neurodegenerative ones. In order to establish S100B as a viable pharmaceutical target, it is critical to understand its mechanistic role in signaling pathways and its interacting partners. In this report, we provide evidence to support a calcium-regulated interaction between S100B and the neuronal calcium sensor protein, neurocalcin delta both in vitro and in living cells. Membrane overlay assays were used to test the interaction between purified proteins in vitro and bimolecular fluorescence complementation assays, for interactions in living cells. Added calcium is essential for interaction in vitro; however, in living cells, calcium elevation causes translocation of the NCALD-S100B complex to the membrane-rich, perinuclear trans-Golgi network in COS7 cells, suggesting that the response is independent of specialized structures/molecules found in neuronal/glial cells. Similar results are also observed with hippocalcin, a closely related paralog; however, the interaction appears less robust in vitro. The N-terminal region of NCALD and HPCA appear to be critical for interaction with S100B based on in vitro experiments. The possible physiological significance of this interaction is discussed. Full article

(This article belongs to the Special Issue Implication of S100 Proteins in Inflammation and Cancer: S100 Proteins as Potential Pharmacological Targets)

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15 pages, 1760 KiB

Open AccessArticle

Circulating Ligands of the Receptor for Advanced Glycation End Products and the Soluble Form of the Receptor Modulate Cardiovascular Cell Apoptosis in Diabetes

by James N. Tsoporis, Erifili Hatziagelaki, Sahil Gupta, Shehla Izhar, Vasileos Salpeas, Anastasia Tsiavou, Angelos G. Rigopoulos, Andreas S. Triantafyllis, John C. Marshall, Thomas G. Parker and Ioannis K. Rizos

Molecules 2020, 25(22), 5235; https://doi.org/10.3390/molecules25225235 - 10 Nov 2020

Cited by 11 | Viewed by 3097

Abstract

We determined whether plasma concentrations of the receptor for advanced glycation end products (RAGE) and the soluble (s) form of RAGE (sRAGE) in healthy individuals and patients with type 2 diabetes (T2D) modulate vascular remodeling. Healthy individuals and patients with T2D were divided [...] Read more.

We determined whether plasma concentrations of the receptor for advanced glycation end products (RAGE) and the soluble (s) form of RAGE (sRAGE) in healthy individuals and patients with type 2 diabetes (T2D) modulate vascular remodeling. Healthy individuals and patients with T2D were divided into two age groups: young = <35 years old or middle-aged (36–64 years old) and stratified based on normal glucose tolerance (NGT), impaired (IGT), and T2D. Plasma titers of sRAGE, the RAGE ligands, AGEs, S100B, S100A1, S100A6, and the apoptotic marker Fas ligand Fas(L) were measured by enzyme-linked immunosorbent assay (ELISA). The apoptotic potential of the above RAGE ligands and sRAGE were assessed in cultured adult rat aortic smooth muscle cells (ASMC). In NGT individuals, aging increased the circulating levels of AGEs and S100B and decreased sRAGE, S100A1 and S100A6. Middle-aged patients with T2D presented higher levels of circulating S100B, AGEs and FasL, but lower levels of sRAGE, S100A1 and S100A6 than individuals with NGT or IGT. Treatment of ASMC with either AGEs or S100B at concentrations detected in T2D patients increased markers of inflammation and apoptosis. Responses attenuated by concomitant administration of sRAGE. In middle-aged patients with T2D, lower circulating plasma levels of sRAGE may limit decoy and exogenous trapping of deleterious pro-apoptotic/pro-inflammatory RAGE ligands AGEs and S100B, increasing the risk for diabetic complications. Full article

(This article belongs to the Special Issue Implication of S100 Proteins in Inflammation and Cancer: S100 Proteins as Potential Pharmacological Targets)

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9 pages, 1337 KiB

Open AccessFeature PaperArticle

Secondary S100B Protein Increase Following Brain Arteriovenous Malformation Rupture is Associated with Cerebral Infarction

by Lorenzo Garzelli, Alice Jacquens, Caroline Amouyal, Kevin Premat, Nader Sourour, Jonathan Cortese, Idriss Haffaf, Bertrand Mathon, Stéphanie Lenck, Frédéric Clarençon, Vincent Degos and Eimad Shotar

Molecules 2020, 25(21), 5177; https://doi.org/10.3390/molecules25215177 - 6 Nov 2020

Cited by 6 | Viewed by 1961

Abstract

Early S100B protein serum elevation is associated with poor prognosis in patients with ruptured brain arteriovenous malformations (BAVM). The purpose of this study is to determine whether a secondary elevation of S100B is associated with early complications or poor outcome in this population. [...] Read more.

Early S100B protein serum elevation is associated with poor prognosis in patients with ruptured brain arteriovenous malformations (BAVM). The purpose of this study is to determine whether a secondary elevation of S100B is associated with early complications or poor outcome in this population. This is a retrospective study of patients admitted for BAVM rupture. A secondary increase of S100B was defined as an absolute increase by 0.1 μg/L within 30 days of admission. Fisher’s and unpaired t tests followed by multivariate analysis were performed to identify markers associated with this increase. Two hundred and twenty-one ruptures met inclusion criteria. Secondary S100B protein serum elevation was found in 17.1% of ruptures and was associated with secondary infarction (p < 0.001), vasospasm-related infarction (p < 0.001), intensive care (p = 0.009), and hospital length of stay (p = 0.005), but not with early rebleeding (p = 0.07) or in-hospital mortality (p = 0.99). Secondary infarction was the only independent predictor of secondary increase of S100B (OR 9.9; 95% CI (3–35); p < 0.001). Secondary elevation of S100B protein serum levels is associated with secondary infarction in ruptured brain arteriovenous malformations. Full article

(This article belongs to the Special Issue Implication of S100 Proteins in Inflammation and Cancer: S100 Proteins as Potential Pharmacological Targets)

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Review

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16 pages, 1585 KiB

Open AccessFeature PaperReview

Pathogenic Roles of S100A8 and S100A9 Proteins in Acute Myeloid and Lymphoid Leukemia: Clinical and Therapeutic Impacts

by Julie Mondet, Simon Chevalier and Pascal Mossuz

Molecules 2021, 26(5), 1323; https://doi.org/10.3390/molecules26051323 - 2 Mar 2021

Cited by 44 | Viewed by 8366

Abstract

Deregulations of the expression of the S100A8 and S100A9 genes and/or proteins, as well as changes in their plasma levels or their levels of secretion in the bone marrow microenvironment, are frequently observed in acute myeloblastic leukemias (AML) and acute lymphoblastic leukemias (ALL). [...] Read more.

Deregulations of the expression of the S100A8 and S100A9 genes and/or proteins, as well as changes in their plasma levels or their levels of secretion in the bone marrow microenvironment, are frequently observed in acute myeloblastic leukemias (AML) and acute lymphoblastic leukemias (ALL). These deregulations impact the prognosis of patients through various mechanisms of cellular or extracellular regulation of the viability of leukemic cells. In particular, S100A8 and S100A9 in monomeric, homodimeric, or heterodimeric forms are able to modulate the survival and the sensitivity to chemotherapy of leukemic clones through their action on the regulation of intracellular calcium, on oxidative stress, on the activation of apoptosis, and thanks to their implications, on cell death regulation by autophagy and pyroptosis. Moreover, biologic effects of S100A8/9 via both TLR4 and RAGE on hematopoietic stem cells contribute to the selection and expansion of leukemic clones by excretion of proinflammatory cytokines and/or immune regulation. Hence, the therapeutic targeting of S100A8 and S100A9 appears to be a promising way to improve treatment efficiency in acute leukemias. Full article

(This article belongs to the Special Issue Implication of S100 Proteins in Inflammation and Cancer: S100 Proteins as Potential Pharmacological Targets)

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