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

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journal contribution
posted on 19.01.2016, 00:00 by Bruno Melillo, Shuaiyi Liang, Jongwoo Park, Arne Schön, Joel R. Courter, Judith M. LaLonde, Daniel J. Wendler, Amy M. Princiotto, Michael S. Seaman, Ernesto Freire, Joseph Sodroski, Navid Madani, Wayne A. Hendrickson, Amos B. Smith
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 (47) 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.