title: Structural determinants for affinity enhancement of a dual antagonist peptide entry inhibitor of human immunodeficiency virus type-1.
abstract: Structure-activity correlations were investigated for substituted peptide conjugates that function as dual receptor site antagonists of HIV-1 gp120. A series of peptide conjugates were constructed via click reaction of both aryl and alkyl acetylenes with an internally incorporated azidoproline 6 derived from the parent peptide 1 (12p1, RINNIPWSEAMM). Compared to 1, many of these conjugates were found to exhibit several orders of magnitude increase in both affinity for HIV-1 gp120 and inhibition potencies at both the CD4 and coreceptor binding sites of gp120. We sought to determine structural factors in the added triazole grouping responsible for the increased binding affinity and antiviral activity of the dual inhibitor conjugates. We measured peptide conjugate potencies in both kinetic and cell infection assays. High affinity was sterically specific, being exhibited by the cis- but not the trans-triazole. The results demonstrate that aromatic, hydrophobic, and steric features in the residue 6 side-chain are important for increased affinity and inhibition. Optimizing these features provides a basis for developing gp120 dual inhibitors into peptidomimetic and increasingly smaller molecular weight entry antagonist leads.
authors.affiliation: Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102, USA.
authors.forename: Hosahudya
authors.initials: H
authors.lastname: Gopi
authors.forename: M
authors.initials: M
authors.lastname: Umashankara
authors.forename: Vanessa
authors.initials: V
authors.lastname: Pirrone
authors.forename: Judith
authors.initials: J
authors.lastname: LaLonde
authors.forename: Navid
authors.initials: N
authors.lastname: Madani
authors.forename: Ferit
authors.initials: F
authors.lastname: Tuzer
authors.forename: Sabine
authors.initials: S
authors.lastname: Baxter
authors.forename: Isaac
authors.initials: I
authors.lastname: Zentner
authors.forename: Simon
authors.initials: S
authors.lastname: Cocklin
authors.forename: Navneet
authors.initials: N
authors.lastname: Jawanda
authors.forename: Shendra R
authors.initials: SR
authors.lastname: Miller
authors.forename: Arne
authors.initials: A
authors.lastname: Schön
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Klein
authors.forename: Ernesto
authors.initials: E
authors.lastname: Freire
authors.forename: Fred C
authors.initials: FC
authors.lastname: Krebs
authors.forename: Amos B
authors.initials: AB
authors.lastname: Smith
authors.forename: Joseph
authors.initials: J
authors.lastname: Sodroski
authors.forename: Irwin
authors.initials: I
authors.lastname: Chaiken
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000378:metabolism; D001665:Binding Sites; D015704:CD4 Antigens / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D015483:HIV Antibodies / Q000378:metabolism; D015699:HIV Envelope Protein gp120 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000276:immunology / Q000502:physiology; D006801:Humans; D018716:Molecular Mimicry; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D053586:Virus Internalization / Q000187:drug effects*
chemical_list: D019380:Anti-HIV Agents; D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D010455:Peptides; D014230:Triazoles; C514793:gp120 protein, Human immunodeficiency virus 1