title: Non-natural peptide triazole antagonists of HIV-1 envelope gp120.
abstract: 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(2), 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(2)) and containing the critical central stereospecific (L)X-(L)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 L-3-benzothienylalanine (Bta) (KR-41), as well as a completely non-natural analogue containing D-amino acid substitutions outside the central cluster (KR-42, (D)Cit-(D)N-(D)N-(D)I-X-Bta-(D)S-CONH(2)), 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, 245 N. 15th Street, New College Building, Room 11302, Philadelphia, PA 19102, USA.
authors.forename: Kantharaju
authors.initials: K
authors.lastname: Kamanna
authors.forename: Rachna
authors.initials: R
authors.lastname: Aneja
authors.forename: Caitlin
authors.initials: C
authors.lastname: Duffy
authors.forename: Pamela
authors.initials: P
authors.lastname: Kubinski
authors.forename: Diogo
authors.initials: D
authors.lastname: Rodrigo Moreira
authors.forename: Lauren D
authors.initials: LD
authors.lastname: Bailey
authors.forename: Karyn
authors.initials: K
authors.lastname: McFadden
authors.forename: Arne
authors.initials: A
authors.lastname: Schön
authors.forename: Andrew
authors.initials: A
authors.lastname: Holmes
authors.forename: Ferit
authors.initials: F
authors.lastname: Tuzer
authors.forename: Mark
authors.initials: M
authors.lastname: Contarino
authors.forename: Ernesto
authors.initials: E
authors.lastname: Freire
authors.forename: Irwin M
authors.initials: IM
authors.lastname: Chaiken
mesh_terms: D000595:Amino Acid Sequence; D019380:Anti-HIV Agents / Q000737:chemistry* / Q000494:pharmacology*; D002151:Calorimetry; D015699:HIV Envelope Protein gp120 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D015497:HIV-1 / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology*; D057786:Peptidomimetics / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology
chemical_list: D019380:Anti-HIV Agents; D015699:HIV Envelope Protein gp120; D010455:Peptides; D057786:Peptidomimetics; D014230:Triazoles