Institute of Molecular Virology, Ulm University Medical Center, 89081, Ulm, Germany.
Dermatology Clinic of the University Medicine of the Johannes Gutenberg University Mainz, 55131, Mainz, Germany.
Commun Biol. 2022 Jul 8;5(1):681. doi: 10.1038/s42003-022-03613-4.
The transmembrane serine protease 2 (TMPRSS2) primes the SARS-CoV-2 Spike (S) protein for host cell entry and represents a promising target for COVID-19 therapy. Here we describe the in silico development and in vitro characterization of peptidomimetic TMPRSS2 inhibitors. Molecular docking studies identified peptidomimetic binders of the TMPRSS2 catalytic site, which were synthesized and coupled to an electrophilic serine trap. The compounds inhibit TMPRSS2 while demonstrating good off-target selectivity against selected coagulation proteases. Lead candidates are stable in blood serum and plasma for at least ten days. Finally, we show that selected peptidomimetics inhibit SARS-CoV-2 Spike-driven pseudovirus entry and authentic SARS-CoV-2 infection with comparable efficacy as camostat mesylate. The peptidomimetic TMPRSS2 inhibitors also prevent entry of recent SARS-CoV-2 variants of concern Delta and Omicron BA.1. In sum, our study reports antivirally active and stable TMPRSS2 inhibitors with prospects for further preclinical and clinical development as antiviral agents against SARS-CoV-2 and other TMPRSS2-dependent viruses.
跨膜丝氨酸蛋白酶 2（TMPRSS2）为 SARS-CoV-2 刺突（S）蛋白进入宿主细胞做了准备，是 COVID-19 治疗的一个有前途的靶点。在这里，我们描述了 TMPRSS2 抑制剂的计算机设计和体外特性。分子对接研究确定了 TMPRSS2 催化位点的肽模拟结合物，这些结合物被合成并与亲电丝氨酸陷阱偶联。这些化合物在抑制 TMPRSS2 的同时，对选定的凝血蛋白酶表现出良好的脱靶选择性。候选药物在血清和血浆中至少稳定十天。最后，我们表明，选定的肽模拟物可抑制 SARS-CoV-2 刺突驱动的假病毒进入和真实 SARS-CoV-2 感染，其功效与卡莫司他甲磺酸盐相当。肽模拟 TMPRSS2 抑制剂还可以阻止最近的 SARS-CoV-2 变体 Delta 和 Omicron BA.1 的进入。总之，我们的研究报告了具有抗病毒活性和稳定性的 TMPRSS2 抑制剂，具有作为针对 SARS-CoV-2 和其他依赖 TMPRSS2 的病毒的抗病毒药物进行进一步临床前和临床开发的前景。
