- freely available
Molecules 2012, 17(10), 12276-12286; doi:10.3390/molecules171012276
Published: 18 October 2012
Abstract: Antimicrobial peptides (AMPs) have been considered as potential therapeutic sources of future antibiotics because of their broad-spectrum activities and different mechanisms of action compared to conventional antibiotics. Although AMPs possess considerable benefits as new generation antibiotics, their clinical and commercial development still have some limitations, such as potential toxicity, susceptibility to proteases, and high cost of peptide production. In order to overcome those obstacles, extensive efforts have been carried out. For instance, unusual amino acids or peptido-mimetics are introduced to avoid the proteolytic degradation and the design of short peptides retaining antimicrobial activities is proposed as a solution for the cost issue. In this review, we focus on small peptides, especially those with less than twelve amino acids, and provide an overview of the relationships between their three-dimensional structures and antimicrobial activities. The efforts to develop highly active AMPs with shorter sequences are also described.
Antimicrobial peptides (AMPs) are endogenous polypeptides produced by multicellular organisms in order to protect a host from pathogenic microbes. AMPs are also defined as host defense peptides because of their essential role in constituting the innate immunity system [1,2,3,4]. AMPs are generally comprised of less than 50 amino acids approximately, and characterized by cationic amphipathic properties. In general, when AMPs are folded in membrane mimetic environments, one side of AMPs is positively charged (mainly due to lysine and arginine residues) and the other side contains a considerable proportion of hydrophobic residues [1,2,5,6].
AMPs show broad-spectrum antimicrobial activities against various microorganisms, including Gram-positive and Gram-negative bacteria, fungi, and viruses . Of particular interest, many AMPs are effective against multi-drug resistant (MDR) bacteria and possess low propensity for developing resistance [7,8,9]. Bacterial resistance to antibiotics can be achieved by diverse routes including inhibition of the drug-target interaction, modification of the drug-binding site in target proteins, and efflux of the drug from target cells . Microorganisms can also alter their genetic patterns in response to environmental changes using their own complex systems called sensor-transducer response systems. For instance, bacteria can modify their gene expression in the presence of AMPs . AMPs possess low propensity for developing resistance, probably due to their distinguished mode of action. Most AMPs, with their amphipathic nature, directly act on the membrane of the pathogen. The cationic properties of AMPs are implicated in their selective interaction with the negatively charged surfaces of microbial membranes, resulting in the accumulation of AMPs on the membrane surface. Then, their hydrophobic portions are responsible for the interaction with hydrophobic components of the membrane. From this complex interaction with the membrane, major rearrangements of its structure occur, which may result from the formation of peptide-lipid specific interactions, the peptide translocation across the membrane and interaction with intracellular targets or the most common mechanism, a membranolytic effect [3,11,12,13,14,15,16]. Such a characteristic mechanism of action, distinct from that of conventional antibiotics, enables AMPs to avoid the common resistance mechanisms observed for classic antibiotics. Consequently, AMPs are receiving great attention as promising alternatives to conventional antibiotics to overcome the current drug resistance crisis. In this review, we describe the advantages and limitations of AMPs as novel antibiotic agents and structural information aids for developing new AMPs. Especially, we focus on small peptides (less than twelve amino acids in length) in clinical trials and their structure-activity relationships (SAR).
2. Structure-Activity Relationships (SAR) of Antimicrobial Peptides
AMPs can be classified into four groups based on their structures: α-helical peptides, β-sheet peptides, extended peptides, and loop peptides [1,2,3,6]. The α-helical AMPs, including magainin, cecropin, and pexiganan, constitute a representative class of AMPs that are the most well established in structure-activity relationships. This group of peptides is usually unstructured in aqueous solution and forms amphipathic helices in membranes or membrane-mimicking environments. Most α-helical AMPs disrupt bacterial membranes, and several mechanisms of action employed by various AMPs have been proposed. The α-helical amphipathic peptides form barrel-like bundles in the bacterial membranes, and these transmembrane clusters line amphipathic pores (barrel-stave model). Many α-helical AMPs, including some magainins and cecropins, can dirupt bacterial membranes by forming carpet-like clusters of peptides. The peptides adsorb and align in parallel to the surface of bacterial membranes, then the membranes are collapsed into micelle-like structures by high concentrations of peptides (carpet model). The α-helical AMPs, such as some magainins and protegrins, form toroidal pores to disrupt the bacterial membranes (toroidal pore model) [1,2,3,4,5,6,7,9,11].
The β-sheet AMPs, such as α-, β-defensins, and protegrin, are stabilized by disulfide bridges, and form relatively rigid structures. Many of β-sheet AMPs exert their antimicrobial activities by disrupting bacterial membranes. They are perpendicularly inserted or tilted into the lipid bilayer to form toroidal pores, and hydrophilic regions of the peptides are associated with the polar head groups of the membranes .
The extended AMPs, which are predominantly rich in specific amino acids such as proline, tryptophan, arginine, and histidine, have no regular secondary structure elements. Indolicidin is a tryptophan/proline-rich extended peptide and Bac5 and Bac7 are proline/arginine-rich peptides [17,18]. Many extended AMPs are not active against the membranes of pathogens, but they can achieve their antimicrobial activities by penetrating across the membranes and interacting with bacterial proteins inside . On the other hand, some extended peptides, such as indolicidin, are membrane active and induce membrane leakage. Indolicidin is a 13-amino acid AMP containing five tryptophan and three proline residues. The peptide adopts a poly-L-II helical structure in the presence of liposomes, and the high content of tryptophan residues is responsible for the interaction with lipid membranes . The loop AMPs, including bactenecin, adopt a loop formation with one disulfide bridge.
Understanding the structure-activity relationships (SAR) of AMPs is essential for the design and development of novel antimicrobial agents with improved properties. In particular, the atomic level structures of AMPs can provide versatile information for all stages of drug development, including the peptide design and modification for pharmaceutical application. Pexiganan (also known as MSI-78), a synthetic variant of magainin 2, is one of the best-investigated AMPs in terms of drug development [19,20]. Pexiganan has reached clinical trials as a novel topical broad-spectrum antibiotic for the treatment of mild-to-moderate diabetic foot ulcer infections [4,20,21]. The three-dimensional structure of pexiganan, determined by Nuclear Magnetic Resonance (NMR) spectroscopy, revealed that the peptide forms a dimeric antiparallel α-helical structure in the presence of membrane mimetics [22,23]. The atomic resolution structure also demonstrated that the side chains of three phenylalanine residues are important for the self-dimerization . In addition to the peptide structure, its orientation in membrane is critical to understand the exact mode of membrane interaction. A solid-state NMR study of pexiganan suggested that the peptide adopts a helical conformation interacting with the membrane surface and then the dimeric peptide is inserted into the membrane .
Knowledge on the functional structures of AMPs also enables a rational design of synthetic model peptides. In this respect, minimalistic de novo approaches to design model amphipathic helical peptides are noteworthy. For example, certain 14- or 15-mer peptides (namely LK peptides) composed of two kinds of amino acids (leucines and lysines), have been characterized as possessing strong antimicrobial activity [24,25]. Then, by introducing a single tryptophan residue at a specific position, 9- to 11-mer LKW peptides could exhibit antimicrobial activity. Now, the de novo designed model peptides remain to be further improved by optimizing the amino acid sequence to enhance stability and to reduce potential toxicity. In addition, their activities need to be checked using clinically isolated bacteria. In the LKW peptide design, the tryptophan residue was specifically incorporated in expectation of structural role for conferring activity . Tryptophan is known to stabilize the helical conformation and membrane interaction of peptides. The specific position where the tryptophan should be incorporated could be determined in the helical wheel projection, by aids of structural information [27,28,29,30]. Three-dimensional structures of engineered peptides could provide useful information for the design of shorter and more potent AMPs. Taken together, all these structural studies contribute to a better understanding of the mechanism of action employed by AMPs, and fine structures of natural and synthetic peptides can be used as a scaffold to generate novel AMPs more suitable for pharmaceutical applications.
3. Antimicrobial Peptides as Potential Therapeutics
AMPs are fascinating targets as novel antibiotics because of their broad-spectrum activity, which include drug-resistant bacteria. Since the isolation of magainins from frog skin in 1987 , there have been many attempts to develop antibiotics from the natural AMPs. However, despite the efforts over more than two decades, there is no AMP agent currently approved by Food and Drug Administration (FDA) [4,32,33]. Although AMPs have considerable advantages for therapeutic applications, including broad-spectrum activity, rapid onset of activity, and relatively low possibility of resistance emergence, they also have some limitations for drug development. The natural AMPs are labile, depending on the surrounding environments, such as the presence of protease, pH change, and so on [34,35,36]. Other obstacles for the use of peptide antibiotics are the potential toxicity of AMPs for oral application and high cost of peptide production . In general, many AMPs are considered to be less toxic to eukaryotes, but systematical toxicity of AMPs for oral application has not been evaluated. In order to overcome those obstacles, many methods have been proposed. For instances, introduction of unusual amino acids (mainly D-form amino acids) or modification of the terminal regions (acetylation or amidation) improved the stability of peptides by preserving them from proteolytic degradation [36,37]. Also, the use of efficient drug delivery systems, such as liposome encapsulation, can be effective for the improvement of the stability and reduction of potential toxicity [38,39]. Presumably, the practical obstacle may be the cost issue. Production costs are estimated to be roughly $50-$400 per 1 gram of amino acid when running commercial quantities . The most certain solution for the high production cost would be the reduction of the peptide size with retention of the activity. Actually, there have been several successful examples of peptide engineering to reduce the peptide size with improved antimicrobial activity. As an example, the inactive, eleven-residue fragment of gaegurin 5 (GGN5N11) could recover the antimicrobial activity by a single tryptophanyl substitution at the hydrophobic-hydrophilic interface of the amphipathic helix [29,30].
4. Small Peptides in Drug Development
4.1. hLF1-11 (Human Lactoferrin 1-11)
Lactoferrin (LF) is an iron-binding glycoprotein which is responsible for part of the innate defense system. The LF can not only bind and trap Fe3+ ion, but also interact with the bacterial membrane directly, which enables the LF to possess antibacterial activity [40,41,42,43]. The synthetic hLF1-11 peptide (GRRRRSVQWCA) is a lactoferrin derivative corresponding to the N-terminal eleven residues of human lactoferrin. The hLF1-11 peptide shows antimicrobial activity against both Gram-positive and -negative bacteria and various fungi. The synthetic peptide is also effective against methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant Acinetobacter baumannii strains [43,44,45]. Moreover, hLF1-11 is active against fluconazole-resistant Candida albicans, and can be used with classic antibiotics for a synergistic effect. Preincubation of fluconazole-resistant C. albicans with hLF1-11 significantly enhances the candidacidal effect of fluconazole .
The three-dimensional structures of several lactoferrin-derived peptides in membrane mimetic conditions have been solved by NMR spectroscopy [47,48,49,50]. The solution structure of LF11 (FQWQRNIRKVR), another N-terminal fragment based on human lactoferrin, showed conformational differences between in an anionic detergent (sodium dodecylsulfate; SDS) and in a zwitterionic detergent (dodecylphosphocholine; DPC) micelles. The structure of LF11 in SDS micelles was well defined and the tryptophan residue was significantly protected in the micelles. However, in DPC micelles, the structure was less defined and the tryptophan residue was less protected . The conformation of hLF1-11 (GRRRRSVQWCA) also varied depending on the environments . Molecular Dynamics (MD) simulation results of hLF1-11 in various solvents suggested that the peptide should be categorized as a loop peptide and adopts a more favorable conformation for the membrane interaction in membrane-mimicking environments. In particular, cationic residues (‑RRRR‑) of the hLF1-11 were rather flexible to be suitable for the interaction with the anionic bacterial membrane. Furthermore, the hydrophobic region, which was positioned approximately perpendicular to the cationic residues, enabled the peptide to bind to the membrane interior. Taken together, all these studies elucidated the structural selectivity of AMPs between bacterial and eukaryotic membranes.
The safety and tolerability of hLF1-11 in healthy volunteers and haematopoietic stem cell transplantation (HSCT) recipients have been tested [43,51]. Intravenous administrations of hLF1-11 were safe and well tolerated in both healthy volunteers and the HSCT recipients. Although some adverse events (AE) were reported, all of them were mild in intensity and reversible. Pharmacodynamic evaluations including cytokine measurements also showed no significant changes in both populations.
4.2. (CKPV)2 Peptide (α-MSH Derivative, also Named CZEN-002)
The α-melanocyte stimulating hormone (α-MSH; SYSMEHFRWGKPV), obtained from the cleavage of pro-opiomelanocortin (POMC), is a neuropeptide hormone showing anti-inflammatory activity and antimicrobial activity [52,53,54]. It is noteworthy that α-MSH peptides are effective against Candida albicans and distinct in action mechanism from other natural AMPs. The candidacidal activity of the α-MSH peptides is caused by increased cyclic adenosine monophosphate (cAMP) in the C. albicans cells , whereas most AMPs kill the bacteria through direct interaction with the bacterial membrane. It has been known that cAMP-mediated modulation is essential for gene expression in C. albicans and the cAMP-activating effect of α-MSH interferes with the cAMP-mediated signaling pathway [56,57].
Interestingly, the C-terminal tripeptide (α-MSH11-13; KPV) also has anti-inflammatory and antimicrobial activities similar to those of the full-length α-MSH [55,58]. The synthetic peptide (CKPV)2, also named CZEN-002, was designed based on the KPV (α-MSH11-13) peptide. The peptide is a dimeric octamer peptide comprising two units of KPV peptide connected by a cysteine-cysteine linker, which is classified as loop peptide. The (CKPV)2 peptide revealed outstanding candidacidal activity against C. krusei and C. glabrata that are emerging as drug-resistant strains, but it showed very low toxicity to host cells [59,60,61]. (CKPV)2 peptide also exerts anti-inflammatory effects as well as the candidacidal activity. It can inhibit TNF-α production with comparable activity to that of the potent α-MSH analogues [60,62].
Because of the simple sequence and small size as well as the excellent candidacidal activity, (CKPV)2 is regarded as a promising agent for development of candidacidal and anti-inflammatory drugs. (CKPV)2 is being currently evaluated in clinical trials for treatment of vulvovaginal candidiasis . In addition, the structure of (CKPV)2 can be a valuable target for the design of other short antimicrobial peptides. Thus, the three-dimensional structure of the (CKPV)2 was determined by NMR spectroscopy, to identify a novel scaffold for the design of small compounds having candidacidal activity . (CKPV)2 adopts a symmetric dimer with an extended backbone structure, which resembles the model structure of natural α-MSH peptide . The overall conformation of (CKPV)2 showed a β-turn-like fold, which may be critically related to the higher activity of (CKPV)2 than KPV monomer .
4.3. P-113 (Histatin 5 Derivative, Also Named PAC113)
Histatin 5, a parent molecule of P-113, is a small cationic peptide secreted into the saliva. Among the histatin family peptides, the histatin 5 exerts the most potent antimicrobial activity against bacteria and fungi [64,65]. The P-113 is an optimized fragment of the histatin 5 comprising twelve residues (residues 4-15 of histatin 5; AKRHHGYKRKFH), and retains antibacterial and anticandidal activity similar to that of the parent molecule, histatin 5 . P-113 has potent candidacidal activity against various strains of C. albicans, C. glabrate, C. parapsilosis, and C. tropocalis that cause oral candidiasis. In addition to the broad spectrum of anticandidal activity, P-113 is also active against fluconazole resistant C. albicans and C. glabrata , which suggests that P-113 can be a promising antifungal agent for the treatment of oral candidiasis.
Structural investigations of hsitatin 5 and P-113 in various solvents have been performed mainly by NMR spectroscopy [67,68,69,70]. The three-dimensional solution structures of histatin 5 revealed that the peptide prefers α-helical conformation in DMSO (dimethyl sulfoxide) or TFE (trifluoroethanol)/water, while it remains unstructured in water [68,69]. However, the helical conformation of histatin 5 in TFE/water system consists of two α-helices, one from Ser2 to Gly9 and the other from Lys11 to His19, whereas a single-alpha helix is formed in DMSO. MD simulation results of histatin 5 also supported that the α-helical regions of the peptide remain structured in the TFE system, but gradually unfold in water . All the data suggest that the adaptation and maintenance of helical structure is essential for the antimicrobial activity of histatin 5.
Structural properties of P-113, which are related to the antimicrobial activity, are also similar to those of histatin 5. Structural conversion of the P-113 from a disordered conformation in aqueous solution to an α-helical conformation in membrane mimetic environments was evidenced by a circular dichroism study [66,67]. The relationships between α-helical propensity and antimicrobial activity of P-113 can be demonstrated by comparing the structures and activities between the free- and metal bound-P-113 peptides. The solution structure of Zn(II)-bound P-113 (Zn(II)-P-113) contains a well defined N-terminal region (from Ala1 to His5) and a less defined C-terminal region (from Gly6 to His12). Imidazole rings of all three His residues (His4, His5, and His12) are coordinating one Zn(II) ion. The involvement of His12 in metal coordination makes the peptide to have lower propensity to adopt an alpha-helical conformation in C-terminal region, therefore resulting in the decrease of antimicrobial activity. The antimicrobial activity of Zn(II)-P-113 against a variety of microorganisms, including S. aureus, E. faecalis, and C. albicans, is much lower than that of metal free P-113 .
The serious problems caused by drug resistant bacteria have created an urgent need for the development of alternative therapeutics. In this respect, AMPs are considered as promising antimicrobial agents for producing new generation antibiotics. Additionally, atomic level structures of AMPs are prerequisite information for the generation of improved peptide antibiotic candidates. Although there are several obstacles to be overcome for clinical applications, natural and synthetic AMPs are still attractive sources to the pharmaceutical companies. In order to facilitate commercial development of peptide antibiotics, it is reasonable to focus on small peptides. Successful generation of short antimicrobial peptide molecules includes the A4W-GGN5N11 [29,30], hLF1-11 [43,44,45,46,47,48,49,50,51], (CKPV)2 [58,59,60,61,62], P-113 [66,67,71], and LKW [24,25,26,27] peptides. In terms of production cost, the use of those peptides would be advantageous in the pharmaceutical field.
This work was supported by the new faculty research fund of Ajou University. This study was supported by the National Research Foundation of Korea (NRF) grant funded by Korean government (MEST) (Grant No. 2012R1A2A1A01003569 & 20110001207). This study was also supported by a grant of the Korea Healthcare technology R&D Project, Ministry for Health, Welfare & Family Affairs, Republic of Korea (Grant No.: A092006). This work was supported in part by 2011 BK21 project for Medicine, Dentistry, and Pharmacy.
- Zasloff, M. Antimicrobial peptides of multicellular organisms. Nature 2002, 415, 389–395. [Google Scholar] [CrossRef]
- Hancock, R.E.; Sahl, H.G. Antimicrobial and host-defense peptides as new anti-infective therapeutic strategies. Nat. Biotechnol. 2006, 24, 1551–1557. [Google Scholar] [CrossRef]
- Nguyen, L.T.; Haney, E.F.; Vogel, H.J. The expanding scope of antimicrobial peptide structures and their modes of action. Trends Biotechnol. 2011, 29, 464–472. [Google Scholar] [CrossRef]
- Fjell, C.D.; Hiss, J.A.; Hancock, R.E.; Schneider, G. Designing antimicrobial peptides: Form follows function. Nat. Rev. Drug Discov. 2012, 11, 37–51. [Google Scholar]
- Hancock, R.E. Peptide antibiotics. Lancet 1997, 349, 418–422. [Google Scholar] [CrossRef]
- Hancock, R.E.; Lehrer, R. Cationic peptides: A new source of antibiotics. Trends Biotechnol. 1998, 16, 82–88. [Google Scholar]
- Marr, A.K.; Gooderham, W.J.; Hancock, R.E. Antibacterial peptides for therapeutic use: Obstacles and realistic outlook. Curr. Opin. Pharmacol. 2006, 6, 468–472. [Google Scholar] [CrossRef]
- Mygind, P.H.; Fischer, R.L.; Schnorr, K.M.; Hansen, M.T.; Sonksen, C.P.; Ludvigsen, S.; Raventos, D.; Buskov, S.; Christensen, B.; De Maria, L.; et al. Plectasin is a peptide antibiotic with therapeutic potential from a saprophytic fungus. Nature 2005, 437, 975–980. [Google Scholar] [CrossRef]
- van’t Hof, W.; Veerman, E.C.; Helmerhorst, E.J.; Amerongen, A.V. Antimicrobial peptides: Properties and applicability. Biol. Chem. 2001, 382, 597–619. [Google Scholar]
- Wright, G.D. Bacterial resistance to antibiotics: Enzymatic degradation and modification. Adv. Drug Deliv. Rev. 2005, 57, 1451–1470. [Google Scholar] [CrossRef]
- Teixeira, V.; Feio, M.J.; Bastos, M. Role of lipids in the interaction of antimicrobial peptides with membranes. Prog. Lipid Res. 2012, 51, 149–177. [Google Scholar] [CrossRef]
- Huang, Y.; Huang, J.; Chen, Y. Alpha-helical cationic antimicrobial peptides: Relationships of structure and function. Protein Cell 2010, 1, 143–152. [Google Scholar] [CrossRef]
- Hancock, R.E.; Chapple, D.S. Peptide antibiotics. Antimicrob. Agents Chemother. 1999, 43, 1317–1323. [Google Scholar]
- Shai, Y.; Oren, Z. From “carpet” mechanism to de-novo designed diastereomeric cell-selective antimicrobial peptides. Peptides 2001, 22, 1629–1641. [Google Scholar] [CrossRef]
- Rotem, S.; Mor, A. Antimicrobial peptide mimics for improved therapeutic properties. Biochim. Biophys. Acta 2009, 1788, 1582–1592. [Google Scholar]
- Hancock, R.E. The bacterial outer membrane as a drug barrier. Trends Microbiol. 1997, 5, 37–42. [Google Scholar] [CrossRef]
- Falla, T.J.; Karunaratne, D.N.; Hancock, R.E. Mode of action of the antimicrobial peptide indolicidin. J. Biol. Chem. 1996, 271, 19298–19303. [Google Scholar] [CrossRef]
- Frank, R.W.; Gennaro, R.; Schneider, K.; Przybylski, M.; Romeo, D. Amino acid sequences of two proline-rich bactenecins. Antimicrobial peptides of bovine neutrophils. J. Biol. Chem. 1990, 265, 18871–18874. [Google Scholar]
- Bessalle, R.; Haas, H.; Goria, A.; Shalit, I.; Fridkin, M. Augmentation of the antibacterial activity of magainin by positive-charge chain extension. Antimicrob. Agents Chemother. 1992, 36, 313–317. [Google Scholar] [CrossRef]
- Gottler, L.M.; Ramamoorthy, A. Structure, Membrane orientation, Mechanism, And function of pexiganan—a highly potent antimicrobial peptide designed from magain. Biochim. Biophys. Acta 2009, 1788, 1680–1686. [Google Scholar] [CrossRef]
- Maloy, W.L.; Kari, U.P. Structure-activity studies on magainins and other host defense peptides. Biopolymers 1995, 37, 105–122. [Google Scholar] [CrossRef]
- Ramamoorthy, A.; Thennarasu, S.; Lee, D.K.; Tan, A.; Maloy, L. Solid-state NMR investigation of the membrane-disrupting mechanism of antimicrobial peptides MSI-78 and MSI-594 derived from magainin 2 and melittin. Biophys. J. 2006, 91, 206–216. [Google Scholar] [CrossRef]
- Porcelli, F.; Buck-Koehntop, B.A.; Thennarasu, S.; Ramamoorthy, A.; Veglia, G. Structures of the dimeric and monomeric variants of magainin antimicrobial peptides (MSI-78 and MSI-594) in micelles and bilayers, determined by NMR spectroscopy. Biochemistry 2006, 45, 5793–5799. [Google Scholar] [CrossRef]
- Blondelle, S.E.; Houghten, R.A. Design of model amphipathic peptides having potent antimicrobial activities. Biochemistry 1992, 31, 12688–12694. [Google Scholar]
- Beven, L.; Castano, S.; Dufourcq, J.; Wieslander, A.; Wroblewski, H. The antibiotic activity of cationic linear amphipathic peptides: Lessons from the action of leucine/lysine copolymers on bacteria of the class Mollicutes. Eur. J. Biochem. 2003, 270, 2207–2217. [Google Scholar] [CrossRef]
- Kang, S.J.; Won, H.S.; Choi, W.S.; Lee, B.J. De novo generation of antimicrobial LK peptides with a single tryptophan at the critical amphipathic interface. J. Pept. Sci. 2009, 15, 583–588. [Google Scholar] [CrossRef]
- Won, H.S.; Kang, S.J.; Lee, B.J. Action mechanism and structural requirements of the antimicrobial peptides, gaegurins. Biochim. Biophys. Acta 2009, 1788, 1620–1629. [Google Scholar] [CrossRef]
- Park, S.H.; Kim, H.E.; Kim, C.M.; Yun, H.J.; Choi, E.C.; Lee, B.J. Role of proline, Cysteine and a disulphide bridge in the structure and activity of the anti-microbial peptide gaegurin 5. Biochem. J. 2002, 368, 171–182. [Google Scholar] [CrossRef]
- Won, H.S.; Jung, S.J.; Kim, H.E.; Seo, M.D.; Lee, B.J. Systematic peptide engineering and structural characterization to search for the shortest antimicrobial peptide analogue of gaegurin 5. J. Biol. Chem. 2004, 279, 14784–14791. [Google Scholar]
- Won, H.S.; Seo, M.D.; Jung, S.J.; Lee, S.J.; Kang, S.J.; Son, W.S.; Kim, H.J.; Park, T.K.; Park, S.J.; Lee, B.J. Structural determinants for the membrane interaction of novel bioactive undecapeptides derived from gaegurin 5. J. Med. Chem. 2006, 49, 4886–4895. [Google Scholar] [CrossRef]
- Zasloff, M. Magainins, A class of antimicrobial peptides from Xenopus skin: Isolation, Characterization of two active forms, And partial cDNA sequence of a precursor. Proc. Natl. Acad. Sci. USA 1987, 84, 5449–5453. [Google Scholar] [CrossRef]
- Gordon, Y.J.; Romanowski, E.G.; McDermott, A.M. A review of antimicrobial peptides and their therapeutic potential as anti-infective drugs. Curr. Eye Res. 2005, 30, 505–515. [Google Scholar] [CrossRef]
- Oyston, P.C.; Fox, M.A.; Richards, S.J.; Clark, G.C. Novel peptide therapeutics for treatment of infections. J. Med. Microbiol. 2009, 58, 977–987. [Google Scholar] [CrossRef]
- Rozek, A.; Powers, J.P.; Friedrich, C.L.; Hancock, R.E. Structure-based design of an indolicidin peptide analogue with increased protease stability. Biochemistry 2003, 42, 14130–14138. [Google Scholar] [CrossRef]
- Lee, I.H.; Cho, Y.; Lehrer, R.I. Effects of pH and salinity on the antimicrobial properties of clavanins. Infect. Immun. 1997, 65, 2898–2903. [Google Scholar]
- John, H.; Maronde, E.; Forssmann, W.G.; Meyer, M.; Adermann, K. N-terminal acetylation protects glucagon-like peptide GLP-1-(7–34)-amide from DPP-IV-mediated degradation retaining cAMP- and insulin-releasing capacity. Eur. J. Med. Res. 2008, 13, 73–78. [Google Scholar]
- McPhee, J.B.; Scott, M.G.; Hancock, R.E. Design of host defence peptides for antimicrobial and immunity enhancing activities. Comb. Chem High. Throughput Screen 2005, 8, 257–272. [Google Scholar] [CrossRef]
- Khaksa, G.; D’Souza, R.; Lewis, S.; Udupa, N. Pharmacokinetic study of niosome encapsulated insulin. Indian J. Exp. Biol. 2000, 38, 901–905. [Google Scholar]
- Samad, A.; Sultana, Y.; Aqil, M. Liposomal drug delivery systems: An update review. Curr. Drug Deliv. 2007, 4, 297–305. [Google Scholar] [CrossRef]
- Sanchez, L.; Calvo, M.; Brock, J.H. Biological role of lactoferrin. Arch. Dis Child. 1992, 67, 657–661. [Google Scholar] [CrossRef]
- Arnold, R.R.; Cole, M.F.; McGhee, J.R. A bactericidal effect for human lactoferrin. Science 1977, 197, 263–265. [Google Scholar]
- Bellamy, W.; Takase, M.; Yamauchi, K.; Wakabayashi, H.; Kawase, K.; Tomita, M. Identification of the bactericidal domain of lactoferrin. Biochim. Biophys. Acta 1992, 1121, 130–136. [Google Scholar] [CrossRef]
- Brouwer, C.P.; Rahman, M.; Welling, M.M. Discovery and development of a synthetic peptide derived from lactoferrin for clinical use. Peptides 2011, 32, 1953–1963. [Google Scholar] [CrossRef]
- Dijkshoorn, L.; Brouwer, C.P.; Bogaards, S.J.; Nemec, A.; van den Broek, P.J.; Nibbering, P.H. The synthetic N-terminal peptide of human lactoferrin, hLF(1–11), Is highly effective against experimental infection caused by multidrug-resistant Acinetobacter baumannii. Antimicrob. Agents Chemother. 2004, 48, 4919–4921. [Google Scholar] [CrossRef]
- Lupetti, A.; Paulusma-Annema, A.; Welling, M.M.; Senesi, S.; van Dissel, J.T.; Nibbering, P.H. Candidacidal activities of human lactoferrin peptides derived from the N terminus. Antimicrob. Agents Chemother. 2000, 44, 3257–3263. [Google Scholar] [CrossRef]
- Lupetti, A.; Paulusma-Annema, A.; Welling, M.M.; Dogterom-Ballering, H.; Brouwer, C.P.; Senesi, S.; Van Dissel, J.T.; Nibbering, P.H. Synergistic activity of the N-terminal peptide of human lactoferrin and fluconazole against Candida species. Antimicrob. Agents Chemother. 2003, 47, 262–267. [Google Scholar] [CrossRef]
- Hwang, P.M.; Zhou, N.; Shan, X.; Arrowsmith, C.H.; Vogel, H.J. Three-dimensional solution structure of lactoferricin B, An antimicrobial peptide derived from bovine lactoferrin. Biochemistry 1998, 37, 4288–4298. [Google Scholar] [CrossRef]
- Japelj, B.; Pristovsek, P.; Majerle, A.; Jerala, R. Structural origin of endotoxin neutralization and antimicrobial activity of a lactoferrin-based peptide. J. Biol. Chem. 2005, 280, 16955–16961. [Google Scholar] [CrossRef]
- Japelj, B.; Zorko, M.; Majerle, A.; Pristovsek, P.; Sanchez-Gomez, S.; Martinez de Tejada, G.; Moriyon, I.; Blondelle, S.E.; Brandenburg, K.; Andra, J.; Lohner, K.; et al. The acyl group as the central element of the structural organization of antimicrobial lipopeptide. J. Am. Chem. Soc. 2007, 129, 1022–1023. [Google Scholar]
- Nguyen, L.T.; Schibli, D.J.; Vogel, H.J. Structural studies and model membrane interactions of two peptides derived from bovine lactoferricin. J. Pept. Sci. 2005, 11, 379–389. [Google Scholar] [CrossRef]
- Velden, W.J.; van Iersel, T.M.; Blijlevens, N.M.; Donnelly, J.P. Safety and tolerability of the antimicrobial peptide human lactoferrin 1–11 (hLF1–11). BMC Med. 2009, 7, 44. [Google Scholar] [CrossRef]
- Rajora, N.; Ceriani, G.; Catania, A.; Star, R.A.; Murphy, M.T.; Lipton, J.M. Alpha-MSH production, Receptors, And influence on neopterin in a human monocyte/macrophage cell line. J. Leuk. Biol. 1996, 59, 248–253. [Google Scholar]
- Catania, A.; Gatti, S.; Colombo, G.; Lipton, J.M. Targeting melanocortin receptors as a novel strategy to control inflammation. Pharmacol. Rev. 2004, 56, 1–29. [Google Scholar] [CrossRef]
- Catania, A.; Colombo, G.; Rossi, C.; Carlin, A.; Sordi, A.; Lonati, C.; Turcatti, F.; Leonardi, P.; Grieco, P.; Gatti, S. Antimicrobial properties of alpha-MSH and related synthetic melanocortins. ScientificWorldJournal 2006, 6, 1241–1246. [Google Scholar] [CrossRef]
- Cutuli, M.; Cristiani, S.; Lipton, J.M.; Catania, A. Antimicrobial effects of alpha-MSH peptides. J. Leuk. Biol. 2000, 67, 233–239. [Google Scholar]
- Harcus, D.; Nantel, A.; Marcil, A.; Rigby, T.; Whiteway, M. Transcription profiling of cyclic AMP signaling in Candida albicans. Mol. Biol. Cell. 2004, 15, 4490–4499. [Google Scholar] [CrossRef]
- Bhattacharya, A.; Datta, A. Effect of cyclic AMP on RNA and protein synthesis in Candida albicans. Biochem. Biophys. Res. Commun. 1977, 77, 1483–1444. [Google Scholar]
- Getting, S.J. Melanocortin peptides and their receptors: New targets for anti-inflammatory therapy. Trends Pharmacol. Sci. 2002, 23, 447–479. [Google Scholar] [CrossRef]
- Catania, A.; Grieco, P.; Randazzo, A.; Novellino, E.; Gatti, S.; Rossi, C.; Colombo, G.; Lipton, J.M. Three-dimensional structure of the alpha-MSH-derived candidacidal peptide [Ac-CKPV]2. J. Pept. Res. 2005, 66, 19–26. [Google Scholar]
- Gatti, S.; Carlin, A.; Sordi, A.; Leonardi, P.; Colombo, G.; Fassati, L.R.; Lipton, J.M.; Catania, A. Inhibitory effects of the peptide (CKPV)2 on endotoxin-induced host reactions. J. Surg. Res. 2006, 131, 209–214. [Google Scholar] [CrossRef]
- Sanglard, D.; Odds, F.C. Resistance of Candida species to antifungal agents: Molecular mechanisms and clinical consequences. Lancet Infect. Dis. 2002, 2, 73–85. [Google Scholar] [CrossRef]
- Capsoni, F.; Ongari, A.; Colombo, G.; Turcatti, F.; Catania, A. The synthetic melanocortin (CKPV)2 exerts broad anti-inflammatory effects in human neutrophils. Peptides 2007, 28, 2016–2022. [Google Scholar] [CrossRef]
- Prabhu, N.V.; Perkyns, J.S.; Pettitt, B.M. Modeling of alpha-MSH conformations with implicit solvent. J. Pept. Res. 1999, 54, 394–407. [Google Scholar] [CrossRef]
- Oppenheim, F.G.; Xu, T.; McMillian, F.M.; Levitz, S.M.; Diamond, R.D.; Offner, G.D.; Troxler, R.F. Histatins, A novel family of histidine-rich proteins in human parotid secretion. Isolation, Characterization, Primary structure, And fungistatic effects on Candida albicans. J. Biol. Chem. 1988, 263, 7472–7477. [Google Scholar]
- Raj, P.A.; Edgerton, M.; Levine, M.J. Salivary histatin 5: Dependence of sequence, Chain length, And helical conformation for candidacidal activity. J. Biol. Chem. 1990, 265, 3898–3905. [Google Scholar]
- Rothstein, D.M.; Spacciapoli, P.; Tran, L.T.; Xu, T.; Roberts, F.D.; Dalla Serra, M.; Buxton, D.K.; Oppenheim, F.G.; Friden, P. Anticandida activity is retained in P-113, A 12-amino-acid fragment of histatin 5. Antimicrob. Agents Chemother. 2001, 45, 1367–1373. [Google Scholar] [CrossRef]
- Raj, P.A.; Soni, S.D.; Levine, M.J. Membrane-induced helical conformation of an active candidacidal fragment of salivary histatins. J. Biol. Chem. 1994, 269, 9610–9619. [Google Scholar]
- Raj, P.A.; Marcus, E.; Sukumaran, D.K. Structure of human salivary histatin 5 in aqueous and nonaqueous solutions. Biopolymers 1998, 45, 51–67. [Google Scholar] [CrossRef]
- Melino, S.; Rufini, S.; Sette, M.; Morero, R.; Grottesi, A.; Paci, M.; Petruzzelli, R. Zn(2+) ions selectively induce antimicrobial salivary peptide histatin-5 to fuse negatively charged vesicles. Identification and characterization of a zinc-binding motif present in the functional domain. Biochemistry 1999, 38, 9626–9633. [Google Scholar]
- Iovino, M.; Falconi, M.; Marcellini, A.; Desideri, A. Molecular dynamics simulation of the antimicrobial salivary peptide histatin-5 in water and in trifluoroethanol: A microscopic description of the water destructuring effect. J. Pept. Res. 2001, 58, 45–55. [Google Scholar] [CrossRef]
- Porciatti, E.; Milenkovic, M.; Gaggelli, E.; Valensin, G.; Kozlowski, H.; Kamysz, W.; Valensin, D. Structural characterization and antimicrobial activity of the Zn(II) complex with P113 (demegen), a derivative of histatin 5. Inorg. Chem. 2010, 49, 8690–8698. [Google Scholar] [CrossRef]
© 2012 by the authors; licensee MDPI, Basel, Switzerland. This article is an open-access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).