A novel small-molecule inhibitor of HIV-1 entry.
BACKGROUND
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.


RESULTS
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.


CONCLUSIONS
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.
Department of Medicine, University of Maryland Baltimore School of Medicine, Baltimore, MD, USA ; Institute of Human Virology, University of Maryland Baltimore School of Medicine, Baltimore, MD, USA.
Alonso
A
Heredia
Department of Microbiology and Immunology, University of Maryland Baltimore School of Medicine, Baltimore, MD, USA ; Institute of Human Virology, University of Maryland Baltimore School of Medicine, Baltimore, MD, USA.
Olga S
OS
Latinovic
Univ Paris Diderot, Sorbonne Paris Cité, ITODYS, UMRCNRS7086, Paris, France.
Florent
F
Barbault
Institute of Human Virology, University of Maryland Baltimore School of Medicine, Baltimore, MD, USA ; Department of Biochemistry and Molecular Biology, University of Maryland Baltimore School of Medicine, Baltimore, MD, USA.
Erik P H
EP
de Leeuw
D052160:Benzothiazoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001665:Binding Sites; D015704:CD4 Antigens / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D015699:HIV Envelope Protein gp120 / Q000378:metabolism; D023581:HIV Fusion Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D015658:HIV Infections / Q000175:diagnosis / Q000188:drug therapy* / Q000821:virology; D015497:HIV-1 / Q000187:drug effects* / Q000472:pathogenicity; D006801:Humans; D007700:Kinetics; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D011485:Protein Binding; D013329:Structure-Activity Relationship; D053586:Virus Internalization / Q000187:drug effects*
D052160:Benzothiazoles; D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120; D023581:HIV Fusion Inhibitors; C514793:gp120 protein, Human immunodeficiency virus 1
CD4; HIV-1; antiviral therapy; defensin; drug; entry