Umumararungu Théoneste, Nyandwi Jean Baptiste, Katandula Jonathan, Twizeyimana Eric, Claude Tomani Jean, Gahamanyi Noël, Ishimwe Nestor, Olawode Emmanuel Oladayo, Habarurema Gratien, Mpenda Matabishi, Uyisenga Jeanne Primitive, Saeed Shamsaldeen Ibrahim
Department of Industrial Pharmacy, School of Medicine and Pharmacy, College of Medicine and Health Sciences, University of Rwanda, Rwanda.
Department of Pharmacology and Toxicology, School of Medicine and Pharmacy, College of Medicine and Health Sciences, University of Rwanda, Rwanda; East African Community Regional Centre of Excellence for Vaccines, Immunization and Health Supply Chain Management, Kigali, Rwanda.
Bioorg Med Chem. 2024 Sep 1;111:117860. doi: 10.1016/j.bmc.2024.117860. Epub 2024 Jul 29.
Human Immunodeficiency Virus (HIV) is the causative agent of Acquired Immunodeficiency Syndrome (AIDS) with high morbidity and mortality rates. Treatment of AIDS/HIV is being complicated by increasing resistance to currently used antiretroviral (ARV) drugs, mainly in low- and middle-income countries (LMICs) due to drug misuse, poor drug supply and poor treatment monitoring. However, progress has been made in the development of new ARV drugs, targeting different HIV components (Fig. 1). This review aims at presenting and discussing the progress made towards the discovery of new ARVs that are at different stages of clinical trials as of July 2024. For each compound, the mechanism of action, target biomolecule, genes associated with resistance, efficacy and safety, class, and phase of clinical trial are discussed. These compounds include analogues of nucleoside reverse transcriptase inhibitors (NRTIs) - islatravir and censavudine; non-nucleoside reverse transcriptase inhibitors (NNRTIs) - Rilpivirine, elsulfavirine and doravirine; integrase inhibitors namely cabotegravir and dolutegravir and chemokine coreceptors 5 and 2 (CC5/CCR2) antagonists for example cenicriviroc. Also, fostemsavir is being developed as an attachment inhibitor while lenacapavir, VH4004280 and VH4011499 are capsid inhibitors. Others are maturation inhibitors such as GSK-254, GSK3532795, GSK3739937, GSK2838232, and other compounds labelled as miscellaneous (do not belong to the classical groups of anti-HIV drugs or to the newer classes) such as obefazimod and BIT225. There is a considerable progress in the development of new anti-HIV drugs and the effort will continue since HIV infections has no cure or vaccine till now. Efforts are needed to reduce the toxicity of available drugs or discover new drugs with new classes which can delay the development of resistance.
人类免疫缺陷病毒（HIV）是获得性免疫缺陷综合征（AIDS）的病原体，发病率和死亡率很高。艾滋病/艾滋病毒的治疗因对目前使用的抗逆转录病毒（ARV）药物的耐药性增加而变得复杂，主要是在低收入和中等收入国家（LMICs），原因包括药物滥用、药物供应不足和治疗监测不力。然而，在开发针对不同HIV成分的新型抗逆转录病毒药物方面已经取得了进展（图1）。本综述旨在介绍和讨论截至2024年7月处于不同临床试验阶段的新型抗逆转录病毒药物的研发进展。对于每种化合物，将讨论其作用机制、靶标生物分子、与耐药性相关的基因、疗效和安全性、类别以及临床试验阶段。这些化合物包括核苷类逆转录酶抑制剂（NRTIs）类似物——islatravir和censavudine；非核苷类逆转录酶抑制剂（NNRTIs）——rilpivirine、elsulfavirine和doravirine；整合酶抑制剂，即卡博特韦和度鲁特韦，以及趋化因子共受体5和2（CC5/CCR2）拮抗剂，例如cenicriviroc。此外，fostemsavir正在作为一种附着抑制剂进行开发，而lenacapavir、VH4004280和VH4011499是衣壳抑制剂。其他的是成熟抑制剂，如GSK-254、GSK3532795、GSK3739937、GSK2838232，以及其他被标记为杂类的化合物（不属于经典的抗HIV药物类别或新类别），如obefazimod和BIT225。新型抗HIV药物的研发取得了相当大的进展，并且这一努力将持续下去，因为迄今为止HIV感染尚无治愈方法或疫苗。需要努力降低现有药物的毒性，或发现具有新类别的新药，以延缓耐药性的发展。
