A novel small-molecule inhibitor of HIV-1 entry

• Published in: Drug design, development and therapy development and therapy, 2015-01, Vol.9 (default), p.5469-5478
• Main Authors: Heredia, Alonso, Latinovic, Olga S, Barbault, Florent, de Leeuw, Erik P H
• Format: Article
• Language: English
• Subjects: Acquired immune deficiency syndrome; AIDS; Antibiotics; Antiretroviral agents; Antiretroviral therapy; Antiviral agents; Antiviral drugs; Automation; Benzothiazoles - chemistry; Benzothiazoles - metabolism; Benzothiazoles - pharmacology; Binding Sites; Biochemistry; CD4 antigen; CD4 Antigens - metabolism; Cell Line; Cell lines; Cell Survival - drug effects; Clinical trials; Dose-Response Relationship, Drug; Drug Design; Drug resistance; Drug therapy; Drugs; Forecasts and trends; Glycoprotein gp120; Heparan sulfate; Highly active antiretroviral therapy; HIV; HIV Envelope Protein gp120 - metabolism; HIV Fusion Inhibitors - chemistry; HIV Fusion Inhibitors - metabolism; HIV Fusion Inhibitors - pharmacology; HIV infection; HIV Infections - diagnosis; HIV Infections - drug therapy; HIV Infections - virology; HIV-1 - drug effects; HIV-1 - pathogenicity; Human immunodeficiency virus; Humans; Infections; Inhibitors; Kinetics; Life expectancy; Life span; Molecular Docking Simulation; Molecular Structure; Original Research; Peptides; Protein Binding; Side effects; Structure-Activity Relationship; Testing; Viral envelope proteins; Virus Internalization - drug effects; Viruses
• ISSN: 1177-8881; 1177-8881
• DOI: 10.2147/DDDT.S89338

Antiretroviral therapy has transformed HIV-1 infection into a managed condition with near-normal life expectancy. However, a significant number of patients remain with limited therapeutic options due to HIV-1 resistance, side effects, or drug costs. Further, it is likely that current drugs will not retain efficacy, due to risks of side effects and transmitted resistance. We describe compound 5660386 (3-ethyl-2-[3-(1,3,3-trimethyl-1,3-dihydro-2H-indol-2-ylidene)-1-propen-1-yl]-1,3-benzothiazol-3-ium) as a novel inhibitor of HIV-1 entry. Compound 5660386 inhibits HIV-1 entry in cell lines and primary cells, binds to HIV-1 envelope protein, and inhibits the interaction of GP120 to CD4. Further, compound 5660386 showed a unique and broad-range activity against primary HIV-1 isolates from different subtypes and geographical areas. Development of small-molecule entry inhibitors of HIV-1 such as 5660386 may lead to novel classes of anti-HIV-1 therapeutics. These inhibitors may be particularly effective against viruses resistant to current antiretroviral drugs and could have potential applications in both treatment and prevention.