Blocking HIV-1 entry by a gp120 surface binding inhibitor

• Published in: Bioorganic & medicinal chemistry letters 2012-05, Vol.22 (9), p.3358-3361
• Main Authors: Tsou, Lun K., Chen, Chin-Ho, Dutschman, Ginger E., Cheng, Yung-Chi, Hamilton, Andrew D.
• Format: Article
• Language: English
• Subjects: Anti-HIV Agents - metabolism; Anti-HIV Agents - pharmacology; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Binding, Competitive; Biological and medical sciences; Calixarene scaffold; drugs; General pharmacology; HIV Envelope Protein gp120 - metabolism; HIV-1 - drug effects; HIV-entry inhibitor; Human immunodeficiency virus 1; Humans; mechanism of action; Medical sciences; Miscellaneous; Pharmacology. Drug treatments; Protein Binding; Protein surface recognition; protein-protein interactions; Proteomimetic inhibitor; Virus Internalization - drug effects; Virus Replication - drug effects; viruses
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2012.02.079

We report the mode of action of a proteomimetic compound that binds to the exterior surface of gp120 and blocks HIV-1 entry into cells. Using a one cycle time-of-addition study and antibody competition binding studies, we have determined that the compound blocks HIV-1 entry through modulation of key protein–protein interactions mediated by gp120. The compound exhibits anti-HIV-1 replication activities against several pseudotype viruses derived from primary isolates and the resistant strains isolated from existing drug candidates with equal potency. Together, these data provide evidence that the proteomimetic compound represents a novel class of HIV-1 viral entry inhibitor that functions through protein surface recognition in analogy to an antibody.