title: Introducing metallocene into a triazole peptide conjugate reduces its off-rate and enhances its affinity and antiviral potency for HIV-1 gp120.
abstract: In this work, we identified a high affinity and potency metallocene-containing triazole peptide conjugate that suppresses the interactions of HIV-1 envelope gp120 at both its CD4 and co-receptor binding sites. The ferrocene-peptide conjugate, HNG-156, was formed by an on-resin copper-catalysed [2+3] cycloaddition reaction. Surface plasmon resonance interaction analysis revealed that, compared to a previously reported phenyl-containing triazole conjugate HNG-105 (105), peptide 156 had a higher direct binding affinity for several subtypes of HIV-1 gp120 due mainly to the decreased dissociation rate of the conjugate-gp120 complex. The ferrocene triazole conjugate bound to gp120 of both clade A (92UG037-08) and clade B (YU-2 and SF162) virus subtypes with nanomolar KD in direct binding and inhibited the binding of gp120 to soluble CD4 and to antibodies that bind to HIV-1YU-2 gp120 at both the CD4 binding site and CD4-induced binding sites. HNG-156 showed a close-to nanomolar IC50 for inhibiting cell infection by HIV-1BaL whole virus. The dual receptor site antagonist activity and potency of HNG-156 make it a promising viral envelope inhibitor lead for developing anti-HIV-1 treatments.
authors.affiliation: Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19102, USA.
authors.forename: Hosahudya
authors.initials: H
authors.lastname: Gopi
authors.forename: Simon
authors.initials: S
authors.lastname: Cocklin
authors.forename: Vanessa
authors.initials: V
authors.lastname: Pirrone
authors.forename: Karyn
authors.initials: K
authors.lastname: McFadden
authors.forename: Ferit
authors.initials: F
authors.lastname: Tuzer
authors.forename: Isaac
authors.initials: I
authors.lastname: Zentner
authors.forename: Sandya
authors.initials: S
authors.lastname: Ajith
authors.forename: Sabine
authors.initials: S
authors.lastname: Baxter
authors.forename: Navneet
authors.initials: N
authors.lastname: Jawanda
authors.forename: Fred C
authors.initials: FC
authors.lastname: Krebs
authors.forename: Irwin M
authors.initials: IM
authors.lastname: Chaiken
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D015704:CD4 Antigens / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D005296:Ferrous Compounds / Q000737:chemistry; D015483:HIV Antibodies / Q000378:metabolism; D015699:HIV Envelope Protein gp120 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D015497:HIV-1 / Q000187:drug effects* / Q000276:immunology; D006801:Humans; D000075163:Metallocenes; D018716:Molecular Mimicry; D009942:Organometallic Compounds / Q000737:chemistry*; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding; D011994:Recombinant Proteins / Q000378:metabolism; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D053586:Virus Internalization / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents; D015704:CD4 Antigens; D005296:Ferrous Compounds; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D000075163:Metallocenes; D009942:Organometallic Compounds; D010446:Peptide Fragments; D011994:Recombinant Proteins; D014230:Triazoles; C514793:gp120 protein, Human immunodeficiency virus 1; C013108:metallocene; C076613:recombinant soluble CD4; C004998:ferrocene