Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012 Jinan, Shandong, P.R. China.
China-Belgium Collaborative Research Center for Innovative Antiviral Drugs of Shandong Province, 44 West Culture Road, 250012 Jinan, Shandong, PR China.
J Med Chem. 2020 May 14;63(9):4837-4848. doi: 10.1021/acs.jmedchem.0c00117. Epub 2020 Apr 22.
The development of efficacious NNRTIs for AIDS therapy commonly encountered the rapid generation of drug-resistant mutations, which becomes a major impediment to effective anti-HIV treatment. Using a structure-based bioisosterism strategy, a series of piperidine-substituted thiophene[2,3-]pyrimidine derivatives were designed and synthesized. Compound yielded the greatest potency, exhibiting significantly better anti-HIV-1 activity than against all of the tested NNRTI-resistant HIV-1 strains. In addition, the phenotypic (cross)resistance of and other NRTIs to the different selected HIV-1 strains was evaluated. As expected, no phenotypic cross-resistance against the NRTIs (AZT and PMPA) was observed with the mutant strain. Furthermore, was identified with improved solubility, lower CYP liability, and hERG inhibition. Remarkably, exhibited optimal pharmacokinetic properties in rats ( = 37.06%) and safety in mice (LD > 2000 mg/kg), which highlights as a promising anti-HIV-1 drug candidate.
高效抗逆转录病毒疗法（Highly active antiretroviral therapy，HAART）是一种通过联合使用多种抗逆转录病毒药物来抑制 HIV 复制的治疗方法，HAART 可以显著降低 HIV 载量，提高 CD4+T 细胞计数，减少 HIV 相关并发症和死亡率。
然而，HAART 也存在一些局限性，如药物副作用、耐药性、药物相互作用、经济负担等。因此，需要不断开发新的抗 HIV 药物，以满足临床需求。
近年来，基于结构的药物设计（Structure-based drug design，SBDD）已经成为一种有效的药物发现方法，可以帮助我们更好地理解药物与靶点之间的相互作用，从而设计出更加高效和特异性的药物。
在抗 HIV 药物的研究中，SBDD 已经取得了一些重要的进展，例如，发现了一些高效的 HIV 蛋白酶抑制剂、HIV 整合酶抑制剂、HIV 逆转录酶抑制剂等。
此外，基于 SBDD 的药物再利用（Drug repurposing）也是一种有效的药物发现方法，可以利用已经上市的药物来治疗新的疾病。在抗 HIV 药物的研究中，已经发现了一些可以用于治疗 HIV 感染的药物，例如，抗疟药氯喹、抗结核药利福平、免疫调节剂干扰素等。
总之，基于结构的药物设计和药物再利用为抗 HIV 药物的研究提供了新的思路和方法，有助于我们开发出更加高效和特异性的抗 HIV 药物，为 HIV 感染的治疗提供更好的选择。
