Department of Pharmaceutical Chemistry, Amity Institute of Pharmacy, Amity University Madhya Pradesh, Gwalior 474005, Madhya Pradesh, India.
Faculty of Pharmacy, Karpagam Academy of Higher Education, Coimbatore 641021, Tamilnadu, India.
Viruses. 2023 Sep 25;15(10):1992. doi: 10.3390/v15101992.
AIDS (acquired immunodeficiency syndrome) is a potentially life-threatening infectious disease caused by human immunodeficiency virus (HIV). To date, thousands of people have lost their lives annually due to HIV infection, and it continues to be a big public health issue globally. Since the discovery of the first drug, Zidovudine (AZT), a nucleoside reverse transcriptase inhibitor (NRTI), to date, 30 drugs have been approved by the FDA, primarily targeting reverse transcriptase, integrase, and/or protease enzymes. The majority of these drugs target the catalytic and allosteric sites of the HIV enzyme reverse transcriptase. Compared to the NRTI family of drugs, the diverse chemical class of non-nucleoside reverse transcriptase inhibitors (NNRTIs) has special anti-HIV activity with high specificity and low toxicity. However, current clinical usage of NRTI and NNRTI drugs has limited therapeutic value due to their adverse drug reactions and the emergence of multidrug-resistant (MDR) strains. To overcome drug resistance and efficacy issues, combination therapy is widely prescribed for HIV patients. Combination antiretroviral therapy (cART) includes more than one antiretroviral agent targeting two or more enzymes in the life cycle of the virus. Medicinal chemistry researchers apply different optimization strategies including structure- and fragment-based drug design, prodrug approach, scaffold hopping, molecular/fragment hybridization, bioisosterism, high-throughput screening, covalent-binding, targeting highly hydrophobic channel, targeting dual site, and multi-target-directed ligand to identify and develop novel NNRTIs with high antiviral activity against wild-type (WT) and mutant strains. The formulation experts design various delivery systems with single or combination therapies and long-acting regimens of NNRTIs to improve pharmacokinetic profiles and provide sustained therapeutic effects.
艾滋病（AIDS）是一种由人类免疫缺陷病毒（HIV）引起的潜在威胁生命的传染病。迄今为止，全球每年都有数千人因 HIV 感染而死亡，它仍然是一个全球性的重大公共卫生问题。自发现第一种药物齐多夫定（AZT）以来，一种核苷逆转录酶抑制剂（NRTI），截至目前，已有 30 种药物获得 FDA 批准，主要针对逆转录酶、整合酶和/或蛋白酶。这些药物大多数针对 HIV 酶逆转录酶的催化和变构部位。与 NRTI 类药物相比，非核苷逆转录酶抑制剂（NNRTI）的化学类别多样，具有特殊的抗 HIV 活性，具有高特异性和低毒性。然而，由于不良反应和多药耐药（MDR）株的出现，目前 NRTI 和 NNRTI 药物的临床应用价值有限。为了克服耐药性和疗效问题，广泛为 HIV 患者开具联合治疗方案。联合抗逆转录病毒疗法（cART）包括一种以上针对病毒生命周期中两种或多种酶的抗逆转录病毒药物。药物化学研究人员应用不同的优化策略，包括基于结构和基于片段的药物设计、前药方法、骨架跃迁、分子/片段杂交、生物等排、高通量筛选、共价结合、靶向高度疏水通道、靶向双位点和多靶点导向配体，以识别和开发具有高抗病毒活性的新型 NNRTIs，针对野生型（WT）和突变株。制剂专家设计了各种单一或联合治疗的给药系统和 NNRTIs 的长效方案，以改善药代动力学特征并提供持续的治疗效果。
