Non‐natural Peptide Triazole Antagonists of HIV‐1 Envelope gp120. Issue 2 (13th December 2012)

• Record Type: Journal Article
• Authors: Kamanna, Kantharaju; Aneja, Rachna; Duffy, Caitlin; Kubinski, Pamela; Rodrigo Moreira, Diogo; Bailey, Lauren D.; McFadden, Karyn; Schön, Arne; Holmes, Andrew; Tuzer, Ferit; Contarino, Mark; Freire, Ernesto; Chaiken, Irwin M.
• Is Part Of: ChemMedChem. Volume 8:Issue 2(2013:Feb.)
• Page Start: 322
• Page End: 328
• Publication Date: 2012-12-13
• Subjects: Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201200422
• Languages: English
• ISSNs: 1860-7179

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <p>We investigated the derivation of non‐natural peptide triazole dual receptor site antagonists of HIV‐1 Env gp120 to establish a pathway for developing peptidomimetic antiviral agents. Previously we found that the peptide triazole HNG‐156 [R‐I‐N‐N‐I‐X‐W‐S‐E‐A‐M‐M‐CONH<sub>2</sub>, in which X=ferrocenyltriazole‐Pro (FtP)] has nanomolar binding affinity to gp120, inhibits gp120 binding to CD4 and the co‐receptor surrogate mAb 17b, and has potent antiviral activity in cell infection assays. Furthermore, truncated variants of HNG‐156, typified by UM‐24 (Cit‐N‐N‐I‐X‐W‐S‐CONH<sub>2</sub>) and containing the critical central stereospecific <sup>L</sup>X‐<sup>L</sup>W cluster, retain the functional characteristics of the parent peptide triazole. In the current work, we examined the possibility of replacing natural with unnatural residue components in UM‐24 to the greatest extent possible. The analogue with the critical "hot spot" residue Trp 6 replaced with <sc>L</sc>‐3‐benzothienylalanine (Bta) (KR‐41), as well as a completely non‐natural analogue containing <sc>D</sc>‐amino acid substitutions outside the central cluster (KR‐42, <sup>D</sup>Cit‐<sup>D</sup>N‐<sup>D</sup>N‐<sup>D</sup>I‐X‐Bta‐<sup>D</sup>S‐CONH<sub>2</sub>), retained the dual receptor site antagonism/antiviral activity signature. The results define differential functional roles of subdomains within the peptide triazole and provide a structural basis for the design of metabolically stable peptidomimetic inhibitors of HIV‐1 Env gp120.</p> </abstract>