一种新型的HIV-1进入小分子抑制剂。
A novel small-molecule inhibitor of HIV-1 entry.
作者信息
Heredia Alonso, Latinovic Olga S, Barbault Florent, de Leeuw Erik P H
机构信息
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.
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.
出版信息
Drug Des Devel Ther. 2015 Oct 1;9:5469-78. doi: 10.2147/DDDT.S89338. eCollection 2015.
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.
CONCLUSION
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.
背景
抗逆转录病毒疗法已将HIV-1感染转变为一种预期寿命接近正常的可控疾病。然而，由于HIV-1耐药性、副作用或药物成本，相当数量的患者治疗选择有限。此外，由于存在副作用和传播性耐药的风险，目前的药物可能无法保持疗效。
结果
我们将化合物5660386（3-乙基-2-[3-(1,3,3-三甲基-1,3-二氢-2H-吲哚-2-亚基)-1-丙烯-1-基]-1,3-苯并噻唑-3-鎓）描述为一种新型的HIV-1进入抑制剂。化合物5660386在细胞系和原代细胞中抑制HIV-1进入，与HIV-1包膜蛋白结合，并抑制GP120与CD4的相互作用。此外，化合物5660386对来自不同亚型和地理区域的原发性HIV-1分离株表现出独特且广泛的活性。
结论
开发如5660386这样的HIV-1小分子进入抑制剂可能会带来新型抗HIV-1治疗药物。这些抑制剂可能对耐当前抗逆转录病毒药物的病毒特别有效，并可能在治疗和预防方面都有潜在应用。
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