Mostashari-Rad Tahereh, Claes Sandra, Schols Dominique, Shirvani Pouria, Fassihi Afshin
Department of Medicinal Chemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran.
Department of Microbiology and Immunology, Rega Institute for Medical Research, Leuven, Belgium.
Curr HIV Res. 2022;20(5):380-396. doi: 10.2174/1570162X20666220628154901.
Although current available medications have increased the quality of life in HIV-infected patients, there are still some shortcomings in HIV treatment arising from viral resistance, drug side effects, and the high cost of medication. Therefore, there is an urgent need for some suitable HIV inhibitors with different mechanisms of action. Gp41, located on the HIV cell surface, plays an important role in the fusion of viral and host cell membranes. With the same structure in different HIV strains, gp41 seems to be a promising target for developing novel HIV fusion inhibitors.
Based on the essential structural elements of gp41 inhibitors, two series of compounds were prepared, and their inhibitory effect on HIV cell growth was investigated. Compared to the known small-molecule gp41 inhibitors, 2-Alkylthio-1-benzylimidazole-5-carboxylic acid (series I) and (E)-4-{[5-(((1-benzyl-1H-1,2,3-triazol-4-yl)methoxyimino)methyl)-2-(alkylthio)-1H-imidazol- 1-yl]methyl}benzoic acid derivatives (series II) were found to have a more flexible skeleton with extra moieties interacting with the gp41 key residues.
In silico drug design approaches, including molecular docking and molecular dynamics simulations, were employed to design these novel compounds prior to preparation. The designed compounds exhibited proper chemical interactions and stable complexes with gp41. Then, the selected candidates were efficiently synthesized, and their anti-HIV-1 and anti-HIV-2 activities, as well as their cellular cytotoxicity in MT-4 cells were determined.
None of the compounds belonging to the series I were active against HIV-1 and HIV-2 replication in cell cultures, and most of the compounds in series II exhibited significant cytotoxicity against MT-4 cells in low micromolar concentrations.
The smaller molecular structures of the compounds in series I might be responsible for their poor anti-HIV effects. The high toxicity of the series II compounds on the host cell makes it impossible to assess their anti-HIV activities.
尽管目前可用的药物提高了HIV感染患者的生活质量，但HIV治疗仍存在一些缺点，如病毒耐药性、药物副作用和药物成本高昂。因此，迫切需要一些作用机制不同的合适的HIV抑制剂。位于HIV细胞表面的糖蛋白41（Gp41）在病毒与宿主细胞膜融合中起重要作用。由于Gp41在不同HIV毒株中结构相同，它似乎是开发新型HIV融合抑制剂的一个有前景的靶点。
基于Gp41抑制剂的基本结构元件，制备了两个系列的化合物，并研究了它们对HIV细胞生长的抑制作用。与已知的小分子Gp41抑制剂相比，发现2-烷硫基-1-苄基咪唑-5-羧酸（系列I）和（E）-4-{[5-(((1-苄基-1H-1,2,3-三唑-4-基)甲氧基亚氨基)甲基)-2-(烷硫基)-1H-咪唑-1-基]甲基}苯甲酸衍生物（系列II）具有更灵活的骨架，且有额外部分与Gp41关键残基相互作用。
在制备之前，采用计算机辅助药物设计方法，包括分子对接和分子动力学模拟，来设计这些新型化合物。所设计的化合物与Gp41表现出适当的化学相互作用和稳定的复合物。然后，高效合成了所选的候选化合物，并测定了它们的抗HIV-1和抗HIV-2活性以及在MT-4细胞中的细胞毒性。
系列I中的化合物在细胞培养中均无抗HIV-1和HIV-2复制的活性，系列II中的大多数化合物在低微摩尔浓度下对MT-4细胞表现出显著的细胞毒性。
系列I中化合物较小的分子结构可能是其抗HIV效果不佳的原因。系列II化合物对宿主细胞的高毒性使得无法评估它们的抗HIV活性。
