Department of Biochemistry, Genetics and Microbiology, Faculty of Natural and Agricultural Sciences, University of Pretoria, Pretoria, 0083, South Africa.
Department of Chemical Sciences, Faculty of Science, Research Centre for Synthesis and Catalysis, University of Johannesburg, Johannesburg, 2006, South Africa.
Biometals. 2022 Aug;35(4):771-784. doi: 10.1007/s10534-022-00400-w. Epub 2022 Jun 14.
Infection by the human immunodeficiency virus, which gives rise to acquired immunodeficiency syndrome, is still a major global health challenge, with millions of people being affected. The use of combination antiretroviral therapy has been a great success, leading to reduced mortality rates over the years. Although successful, these drugs are associated with various side effects, necessitating the development of new treatment strategies. This study investigated three metal-based complexes that were previously shown to possess some anticancer activity. The complexes were investigated against three pseudoviruses, which consisted of HIV-1 subtype C (CAP 210 and Du 156) and subtype A (Q 23). These complexes inhibited viral entry at low micromolar concentrations, with IC values ranging from 5.34 to 7.41 µM for N-aryl-1H-1,2,3-triazole-based cyclometalated ruthenium-(II) (A), 2.35-8.09 µM for N-aryl-1H-1,2,3-triazole-based cyclometalated iridium-(III) (B) and 2.59-4.18 µM for N-aryl-1H-1,2,3-triazole-based cyclometalated osmium-(II) complex (C). This inhibition was significant, with no significant inhibition from the ligand alone at similar concentrations. Additionally, these concentrations were non-toxic to mammalian cells. The complexes were further analysed for their potential mechanism of action using in silico docking (Maestro 12.2), which indicated that the activity is potentially due to their interaction with the CCR5 co-receptor. The predicted interaction involved amino acids (Glu 283, Tyr 251 and Tyr 108) that are essential for the interaction of the chemokine receptor with viral gp120.
感染导致获得性免疫缺陷综合征的人类免疫缺陷病毒仍然是一个主要的全球健康挑战，数百万人受到影响。联合抗逆转录病毒疗法的使用取得了巨大成功，导致多年来死亡率降低。尽管取得了成功，但这些药物与各种副作用相关，需要开发新的治疗策略。本研究调查了三种先前显示具有一些抗癌活性的金属基配合物。这些配合物针对三种假病毒进行了研究，这些假病毒由 HIV-1 亚型 C（CAP 210 和 Du 156）和亚型 A（Q 23）组成。这些配合物以低微摩尔浓度抑制病毒进入，IC 值范围为 5.34 至 7.41µM 的 N-芳基-1H-1,2,3-三唑基环金属化钌-(II)（A）、2.35-8.09µM 的 N-芳基-1H-1,2,3-三唑基环金属化铱-(III)（B）和 2.59-4.18µM 的 N-芳基-1H-1,2,3-三唑基环金属化锇-(II)配合物（C）。这种抑制作用很显著，在类似浓度下，单独的配体没有明显的抑制作用。此外，这些浓度对哺乳动物细胞没有毒性。这些配合物进一步通过计算机对接（Maestro 12.2）分析其潜在的作用机制，表明其活性可能是由于它们与 CCR5 辅助受体的相互作用。预测的相互作用涉及到一些对趋化因子受体与病毒 gp120 相互作用至关重要的氨基酸（Glu 283、Tyr 251 和 Tyr 108）。
