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Identification of gp120 Residue His105 as a Novel Target for HIV-1 Neutralization by Small-Molecule CD4-Mimics.


ABSTRACT: The design and synthesis of butyl chain derivatives at the indane ring 3-position of our lead CD4-mimetic compound BNM-III-170 that inhibits human immunodeficiency virus (HIV-1) infection are reported. Optimization efforts were guided by crystallographic and computational analysis of the small-molecule ligands of the Phe43 cavity of the envelope glycoprotein gp120. Biological evaluation of 11-21 revealed that members of this series of CD4-mimetic compounds are able to inhibit HIV-1 viral entry into target cells more potently and with greater breadth compared to BNM-III-170. Crystallographic analysis of the binding pocket of 14, 16, and 17 revealed a novel hydrogen bonding interaction between His105 and a primary hydroxyl group on the butyl side chain. Further optimization of this interaction with the His105 residue holds the promise of more potent CD4-mimetic compounds.

SUBMITTER: Fritschi CJ 

PROVIDER: S-EPMC8591726 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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Identification of gp120 Residue His105 as a Novel Target for HIV-1 Neutralization by Small-Molecule CD4-Mimics.

Fritschi Christopher J CJ   Liang Shuaiyi S   Mohammadi Mohammadjavad M   Anang Saumya S   Moraca Francesca F   Chen Junhua J   Madani Navid N   Sodroski Joseph G JG   Abrams Cameron F CF   Hendrickson Wayne A WA   Smith Amos B AB  

ACS medicinal chemistry letters 20211029 11


The design and synthesis of butyl chain derivatives at the indane ring 3-position of our lead CD4-mimetic compound BNM-III-170 that inhibits human immunodeficiency virus (HIV-1) infection are reported. Optimization efforts were guided by crystallographic and computational analysis of the small-molecule ligands of the Phe43 cavity of the envelope glycoprotein gp120. Biological evaluation of <b>11</b>-<b>21</b> revealed that members of this series of CD4-mimetic compounds are able to inhibit HIV-1  ...[more]

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