Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) brutally perils physical and mental health worldwide. Unavailability of effective anti-viral drug rendering global threat of COVID-19 caused by SARS-CoV-2. In this scenario, viral protease enzymes are crucial targets for drug discovery. This extensive study meticulously focused on two viral proteases such as main protease (Mpro) and papain-like protease (PLpro), those are essential for viral replication. This review provides a detail overview of the targets (Mpro and PLpro) from a structural and medicinal chemistry point of view, together with recently reported protease inhibitors. An insight into the challenges in the development of effective as well as drug like protease inhibitors is discussed. Peptidomimetic and/or covalent coronavirus protease inhibitors possessed potent and selective active site inhibition but compromised in pharmacokinetic parameters to be a drug/drug like molecule. Lead optimization of non-peptidomimetic and/or low molecular weight compounds may be a better option for oral delivery. A masterly combination of adequate pharmacokinetic properties with coronavirus protease activity as well as selectivity will provide potential drug candidates in future. This study is a part of our endeavors which surely dictates medicinal chemistry efforts to discover effective anti-viral agent for this devastating disease.

严重的急性呼吸综合症冠状病毒2（SARS-CoV-2）残酷地危害着全世界的身心健康。没有有效的抗病毒药物引起SARS-CoV-2引起的全球COVID-19威胁。在这种情况下，病毒蛋白酶是药物发现的关键目标。这项广泛的研究一丝不苟地集中在两种病毒蛋白酶上，例如主蛋白酶（Mpro）和木瓜蛋白酶样蛋白酶（PLpro），它们对于病毒复制是必不可少的。这篇综述从结构和药物化学的角度提供了靶标（Mpro和PLpro）的详细概述，以及最近报道的蛋白酶抑制剂。讨论了对开发有效的以及类似药物的蛋白酶抑制剂的挑战的见解。拟肽和/或共价冠状病毒蛋白酶抑制剂具有有效的和选择性的活性位点抑制作用，但药代动力学参数受到损害，成为药物/药物样分子。非拟肽和/或低分子量化合物的前导优化可能是口服给药的更好选择。足够的药代动力学特性与冠状病毒蛋白酶活性以及选择性的完美结合将为将来提供潜在的候选药物。这项研究是我们努力的一部分，肯定会决定药物化学努力以发现针对这种破坏性疾病的有效抗病毒剂。非拟肽和/或低分子量化合物的前导优化可能是口服给药的更好选择。足够的药代动力学特性与冠状病毒蛋白酶活性以及选择性的完美结合将为将来提供潜在的候选药物。这项研究是我们努力的一部分，肯定会决定药物化学努力以发现针对这种破坏性疾病的有效抗病毒剂。非拟肽和/或低分子量化合物的前导优化可能是口服给药的更好选择。足够的药代动力学特性与冠状病毒蛋白酶活性以及选择性的完美结合将为将来提供潜在的候选药物。这项研究是我们努力的一部分，肯定会决定药物化学努力以发现针对这种破坏性疾病的有效抗病毒剂。