Host defense peptides (HDPs) are a critical component of innate immunity and a first line of defence against infection by a broad spectrum of pathogens. The broad family of HDPs stabilized by cysteine bridges shares a common structural signature, the γ-core motif, which may represent an archetypal membrane-binding domain present in a common ancestor[1]. Human β-defensins (HBDs) are defined by a conserved triple-disulfide scaffold with C1 –C5 , C2 –C4 and C3 –C6 connectivities, with otherwise little sequence conservation among species. The γ-core of HBD3 is enclosed in a 19-aa β-hairpin stabilized by the C3 –C6 disulphide. We found that the HBD3 β-hairpin is the folding nucleus of the molecule and when extracted as an isolated peptide, it rapidly and spontaneously forms the disulphide[2]. The HBD3 β-hairpin displays a remarkable stability in human serum, has comparable potency to HBD3 against gram-negative and gram-positive bacteria, binds to CD98, which mediates HBD3 internalization in eukaryotic cells[3], and has antiviral activity against HIV and HSV, while being non-toxic to human cells[2]. These results demonstrate that the γ-core-containing β-hairpin of HBD3 is the evolutionary starting point of the full-length molecule, and a viable HDP per se. We propose that this small stable structural scaffold, which is preserved in spite of a high level of sequence variability, represents a privileged structure for the design of antimicrobial agents. First introduced for small molecule drugs, the concept of privileged structures, chemical scaffolds from which ligands can be derived for several different receptors, is even more relevant for biomolecules, because of the co-evolution of receptors and their ligands. Accordingly, a conotoxin with a singledisulfide β-hairpin structure highly similar to the HBD3 γ-core has been recently identified[4].

Host Defense Peptide-derived Privileged Scaffolds for Anti-infective Drug Discovery / Nigro, Ersilia; Colavita, Irene; Sarnataro, Daniela; Scudiero, Olga; Zambrano, G.; Granata, V.; Daniele, A.; Carotenuto, Alfonso; Galdiero, Stefania; Folliero, Vincenzo; Galdiero, M.; Urbanowicz, R. A.; Ball, J. K.; Salvatore, F.; Pessi, A.. - 1:(2016). (Intervento presentato al convegno 15th Naples Workshop on Bioactive Peptides tenutosi a Napoli nel 23-25 Giugno 2016).

Host Defense Peptide-derived Privileged Scaffolds for Anti-infective Drug Discovery

NIGRO, ERSILIA;COLAVITA, IRENE;SARNATARO, DANIELA;SCUDIERO, OLGA;Daniele, A.;CAROTENUTO, ALFONSO;GALDIERO, STEFANIA;FOLLIERO, VINCENZO;
2016

Abstract

Host defense peptides (HDPs) are a critical component of innate immunity and a first line of defence against infection by a broad spectrum of pathogens. The broad family of HDPs stabilized by cysteine bridges shares a common structural signature, the γ-core motif, which may represent an archetypal membrane-binding domain present in a common ancestor[1]. Human β-defensins (HBDs) are defined by a conserved triple-disulfide scaffold with C1 –C5 , C2 –C4 and C3 –C6 connectivities, with otherwise little sequence conservation among species. The γ-core of HBD3 is enclosed in a 19-aa β-hairpin stabilized by the C3 –C6 disulphide. We found that the HBD3 β-hairpin is the folding nucleus of the molecule and when extracted as an isolated peptide, it rapidly and spontaneously forms the disulphide[2]. The HBD3 β-hairpin displays a remarkable stability in human serum, has comparable potency to HBD3 against gram-negative and gram-positive bacteria, binds to CD98, which mediates HBD3 internalization in eukaryotic cells[3], and has antiviral activity against HIV and HSV, while being non-toxic to human cells[2]. These results demonstrate that the γ-core-containing β-hairpin of HBD3 is the evolutionary starting point of the full-length molecule, and a viable HDP per se. We propose that this small stable structural scaffold, which is preserved in spite of a high level of sequence variability, represents a privileged structure for the design of antimicrobial agents. First introduced for small molecule drugs, the concept of privileged structures, chemical scaffolds from which ligands can be derived for several different receptors, is even more relevant for biomolecules, because of the co-evolution of receptors and their ligands. Accordingly, a conotoxin with a singledisulfide β-hairpin structure highly similar to the HBD3 γ-core has been recently identified[4].
2016
Host Defense Peptide-derived Privileged Scaffolds for Anti-infective Drug Discovery / Nigro, Ersilia; Colavita, Irene; Sarnataro, Daniela; Scudiero, Olga; Zambrano, G.; Granata, V.; Daniele, A.; Carotenuto, Alfonso; Galdiero, Stefania; Folliero, Vincenzo; Galdiero, M.; Urbanowicz, R. A.; Ball, J. K.; Salvatore, F.; Pessi, A.. - 1:(2016). (Intervento presentato al convegno 15th Naples Workshop on Bioactive Peptides tenutosi a Napoli nel 23-25 Giugno 2016).
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/666596
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