| Title | Introducing metallocene into a triazole peptide conjugate reduces its off-rate and enhances its affinity and antiviral potency for HIV-1 gp120. | | Author(s) | Gopi H, Cocklin S, Pirrone V, McFadden K, Tuzer F, Zentner I, Ajith S, Baxter S, Jawanda N, Krebs FC, Chaiken IM | | Institution | Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19102, USA. | | Source | J Mol Recognit 2008 May 22. | | 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 K(D) in direct binding and inhibited the binding of gp120 to soluble CD4 and to antibodies that bind to HIV-1(YU-2) gp120 at both the CD4 binding site and CD4-induced binding sites. HNG-156 showed a close-to nanomolar IC(50) for inhibiting cell infection by HIV-1(BaL) 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. Copyright (c) 2008 John Wiley & Sons, Ltd. | | Language | ENG | | Pub Type(s) | JOURNAL ARTICLE
| | PubMed ID | 18498083 |
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