Small-Molecule CD4-Mimics: Structure-Based Optimization of HIV-1 Entry Inhibition

Melillo, Bruno; Liang, Shuaiyi; Park, Jongwoo; Schön, Arne; Courter, Joel R.; LaLonde, Judith M.; Wendler, Daniel J.; Princiotto, Amy M.; Seaman, Michael S.; Freire, Ernesto; Sodroski, Joseph; Madani, Navid; Hendrickson, Wayne A.; Smith III, Amos B.

doi:10.1021/acsmedchemlett.5b00471

Small-Molecule CD4-Mimics: Structure-Based Optimization of HIV-1 Entry Inhibition

Journal Article · Tue Jan 19 00:00:00 EST 2016 · ACS Medicinal Chemistry Letters

DOI:https://doi.org/10.1021/acsmedchemlett.5b00471· OSTI ID:1245880

Melillo, Bruno ^[1]; Liang, Shuaiyi ^[2]; Park, Jongwoo ^[1]; Schön, Arne ^[3]; Courter, Joel R. ^[1]; LaLonde, Judith M. ^[4]; Wendler, Daniel J. ^[1]; Princiotto, Amy M. ^[5]; Seaman, Michael S. ^[5]; Freire, Ernesto ^[3]; Sodroski, Joseph ^[6]; Madani, Navid ^[5]; Hendrickson, Wayne A. ^[2]; Smith III, Amos B. ^[1]

Univ. of Pennsylvania, Philadelphia, PA (United States)
Columbia Univ., New York, NY (United States)
Johns Hopkins Univ., Baltimore, MD (United States)
Bryn Mawr College, PA (United States)
Harvard Medical School, Boston, MA (United States)
Harvard Medical School, Boston, MA (United States); Harvard School of Public Health, Boston, MA (United States)

We report the optimization, based on computational, thermodynamic, and crystallographic data, of a series of small-molecule ligands of the Phe43 cavity of the envelope glycoprotein gp120 of human immunodeficiency virus (HIV) has been achieved. Importantly, biological evaluation revealed that the small-molecule CD4 mimics (4–7) inhibit HIV-1 entry into target cells with both significantly higher potency and neutralization breadth than previous congeners, while maintaining high selectivity for the target virus. Their binding mode was characterized via thermodynamic and crystallographic studies.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: National Institutes of Health (NIH); USDOE Office of Science (SC)

OSTI ID:: 1245880

Journal Information:: ACS Medicinal Chemistry Letters, Journal Name: ACS Medicinal Chemistry Letters Journal Issue: 3 Vol. 7; ISSN 1948-5875

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Molecular design opportunities presented by solvent‐exposed regions of target proteins Jiang, Xiangyi; Yu, Ji; Zhou, Zhongxia Medicinal Research Reviews, Vol. 39, Issue 6 https://doi.org/10.1002/med.21581	journal	April 2019
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The Discovery and Development of Oxalamide and Pyrrole Small Molecule Inhibitors of gp120 and HIV Entry - A Review Motati, Damoder Reddy; Uredi, Dilipkumar; Watkins, E. Blake Current Topics in Medicinal Chemistry, Vol. 19, Issue 18 https://doi.org/10.2174/1568026619666190717163959	journal	October 2019

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