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Potentiation of Drug Toxicity through Virus Latency Reversal Promotes Preferential Elimination of HIV Infected Cells
Advanced Therapeutics ( IF 4.6 ) Pub Date : 2022-08-22 , DOI: 10.1002/adtp.202200113
Thanh Tung Truong 1 , Manuel Hayn 2 , Camilla Kaas Frich 1 , Lia‐Raluca Olari 2 , Lucy Kate Ladefoged 3 , Morten T. Jarlstad Olesen 2 , Josefine H. Jakobsen 1 , Cherie K. Lunabjerg‐Vestergaard 1 , Birgit Schiøtt 1, 4 , Jan Münch 2 , Alexander N. Zelikin 1, 4
Affiliation  

Eliminating latently infected cells is a highly challenging, indispensable step toward the cure for HIV/AIDS. Hypothesis put forward herein is that the unique HIV protease cut site (Phe-Pro) can be reconstructed using a potent inhibitor of tubulin polymerization, monomethyl auristatin F (MMAF), which features Phe at its C-terminus. This presents opportunities to design prodrugs that are specifically activated by the HIV protease. To this end, a series of MMAF derivatives is synthesized and evaluated in cell culture using latently HIV-infected cells. The cytotoxicity of compounds is indeed enhanced upon latency reversal by up to 11-fold. As a result, in a mixed cell population, nanomolar concentrations of the lead compounds depletes predominantly the HIV-infected cells and in doing so markedly enriches the pool of the uninfected cells. Affinity of the lead compounds to the viral protease is validated computationally and experimentally but despite expectations, the mechanism of action of the synthesized toxins is shown to be independent from the enzymatic activity of the HIV protease.

中文翻译:

通过病毒潜伏期逆转增强药物毒性促进优先消除 HIV 感染细胞

消除潜伏感染的细胞是治愈 HIV/AIDS 的一个极具挑战性且不可或缺的步骤。本文提出的假设是,可以使用一种有效的微管蛋白聚合抑制剂、单甲基 auristatin F (MMAF) 重建独特的 HIV 蛋白酶切割位点 (Phe-Pro),其在其 C 末端具有 Phe。这为设计由 HIV 蛋白酶特异性激活的前药提供了机会。为此,使用潜伏感染 HIV 的细胞在细胞培养物中合成和评估了一系列 MMAF 衍生物。化合物的细胞毒性在潜伏期逆转后确实增强了多达 11 倍。结果,在混合细胞群中,纳摩尔浓度的先导化合物主要耗尽了 HIV 感染的细胞,并在这样做时显着丰富了未感染细胞的池。
更新日期:2022-08-22
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