Abstract：
BACKGROUND: Neglected tropical diseases are a severe burden for mankind, affecting an increasing number of people around the globe. Many of those diseases are caused by protozoan parasites in which cysteine proteases play a key role in the parasite\'s pathogenesis.
OBJECTIVE: In this review article, we summarize the drug discovery efforts of the research community from 2017 - 2022 with a special focus on the optimization of small molecule cysteine protease inhibitors in terms of selectivity profiles or drug-like properties as well as in vivo studies. The cysteine proteases evaluated by this methodology include Cathepsin B1 from Schistosoma mansoni, papain, cruzain, falcipain, and rhodesain.
METHODS: Exhaustive literature searches were performed using the keywords \"Cysteine Proteases\" and \"Neglected Tropical Diseases\" including the years 2017 - 2022. Overall, approximately 3\'000 scientific papers were retrieved, which were filtered using specific keywords enabling the focus on drug discovery efforts.
CONCLUSIONS: Potent and selective cysteine protease inhibitors to treat neglected tropical diseases were identified, which progressed to pharmacokinetic and in vivo efficacy studies. As far as the authors are aware of, none of those inhibitors reached the stage of active clinical development. Either the inhibitor\'s potency or pharmacokinetic properties or safety profile or a combination thereof prevented further development of the compounds. More efforts with particular emphasis on optimizing pharmacokinetic and safety properties are needed, potentially by collaborations of academic and industrial research groups with complementary expertise. Furthermore, new warheads reacting with the catalytic cysteine should be exploited to advance the research field in order to make a meaningful impact on society.
OBJECTIVE: In this review article, we summarize the drug discovery efforts of the research community from 2017 - 2022 with a special focus on the optimization of small molecule cysteine protease inhibitors in terms of selectivity profiles or drug-like properties as well as in vivo studies. The cysteine proteases evaluated by this methodology include Cathepsin B1 from Schistosoma mansoni, papain, cruzain, falcipain, and rhodesain.
METHODS: Exhaustive literature searches were performed using the keywords \"Cysteine Proteases\" and \"Neglected Tropical Diseases\" including the years 2017 - 2022. Overall, approximately 3\'000 scientific papers were retrieved, which were filtered using specific keywords enabling the focus on drug discovery efforts.
CONCLUSIONS: Potent and selective cysteine protease inhibitors to treat neglected tropical diseases were identified, which progressed to pharmacokinetic and in vivo efficacy studies. As far as the authors are aware of, none of those inhibitors reached the stage of active clinical development. Either the inhibitor\'s potency or pharmacokinetic properties or safety profile or a combination thereof prevented further development of the compounds. More efforts with particular emphasis on optimizing pharmacokinetic and safety properties are needed, potentially by collaborations of academic and industrial research groups with complementary expertise. Furthermore, new warheads reacting with the catalytic cysteine should be exploited to advance the research field in order to make a meaningful impact on society.
摘要：
背景：被忽视的热带病是人类的沉重负担，影响着全球越来越多的人。这些疾病中的许多是由原生动物寄生虫引起的,其中半胱氨酸蛋白酶在寄生虫的发病机理中起着关键作用。
目的：在这篇综述中，我们总结了2017-2022年研究界的药物发现工作,特别关注小分子半胱氨酸蛋白酶抑制剂在选择性谱或药物样特性方面的优化以及体内研究等活动.通过这种方法评估的半胱氨酸蛋白酶包括来自曼氏血吸虫的组织蛋白酶B1，木瓜蛋白酶,Cruzain,falcipain,还有Rhodesain.
方法：使用关键词“半胱氨酸蛋白酶”和“被忽视的热带病”进行详尽的文献检索，包括2017-2022年。总的来说,检索到大约3000篇科学论文，使用特定的关键字进行过滤，从而可以专注于药物发现工作。
结论：确定了治疗被忽视的热带病的有效和选择性半胱氨酸蛋白酶抑制剂，进展到药代动力学和体内疗效研究。据作者所知，这些抑制剂均未达到积极的临床开发阶段。抑制剂的效力或药代动力学性质或安全性特征或其组合阻止了化合物的进一步发展。需要更多的努力，特别强调优化药代动力学和安全特性，可能是由具有互补专业知识的学术和工业研究小组合作。此外，应该利用与催化半胱氨酸反应的新型弹头来推进研究领域，以便对社会产生有意义的影响。
目的：在这篇综述中，我们总结了2017-2022年研究界的药物发现工作,特别关注小分子半胱氨酸蛋白酶抑制剂在选择性谱或药物样特性方面的优化以及体内研究等活动.通过这种方法评估的半胱氨酸蛋白酶包括来自曼氏血吸虫的组织蛋白酶B1，木瓜蛋白酶,Cruzain,falcipain,还有Rhodesain.
方法：使用关键词“半胱氨酸蛋白酶”和“被忽视的热带病”进行详尽的文献检索，包括2017-2022年。总的来说,检索到大约3000篇科学论文，使用特定的关键字进行过滤，从而可以专注于药物发现工作。
结论：确定了治疗被忽视的热带病的有效和选择性半胱氨酸蛋白酶抑制剂，进展到药代动力学和体内疗效研究。据作者所知，这些抑制剂均未达到积极的临床开发阶段。抑制剂的效力或药代动力学性质或安全性特征或其组合阻止了化合物的进一步发展。需要更多的努力，特别强调优化药代动力学和安全特性，可能是由具有互补专业知识的学术和工业研究小组合作。此外，应该利用与催化半胱氨酸反应的新型弹头来推进研究领域，以便对社会产生有意义的影响。
