Independent Researcher, Boston, MA, United States.
Comput Biol Chem. 2022 Jun;98:107671. doi: 10.1016/j.compbiolchem.2022.107671. Epub 2022 Mar 28.
A novel coronavirus (SARS-CoV-2) has devastated the globe as a pandemic that has killed millions of people. Widespread vaccination is still uncertain, so many scientific efforts have been directed toward discovering antiviral treatments. Many drugs are being investigated to inhibit the coronavirus main protease, 3CLpro, from cleaving its viral polyprotein, but few publications have addressed this protease's interactions with the host proteome or their probable contribution to virulence. Too few host protein cleavages have been experimentally verified to fully understand 3CLpro's global effects on relevant cellular pathways and tissues. Here, I set out to determine this protease's targets and corresponding potential drug targets. Using a neural network trained on cleavages from 392 coronavirus proteomes with a Matthews correlation coefficient of 0.985, I predict that a large proportion of the human proteome is vulnerable to 3CLpro, with 4898 out of approximately 20,000 human proteins containing at least one putative cleavage site. These cleavages are nonrandomly distributed and are enriched in the epithelium along the respiratory tract, brain, testis, plasma, and immune tissues and depleted in olfactory and gustatory receptors despite the prevalence of anosmia and ageusia in COVID-19 patients. Affected cellular pathways include cytoskeleton/motor/cell adhesion proteins, nuclear condensation and other epigenetics, host transcription and RNAi, ribosomal stoichiometry and nascent-chain detection and degradation, ubiquitination, pattern recognition receptors, coagulation, lipoproteins, redox, and apoptosis. This whole proteome cleavage prediction demonstrates the importance of 3CLpro in expected and nontrivial pathways affecting virulence, lead me to propose more than a dozen potential therapeutic targets against coronaviruses, and should therefore be applied to all viral proteases and subsequently experimentally verified.
一种新型冠状病毒（SARS-CoV-2）已在全球范围内引发大流行，导致数百万人死亡。广泛接种疫苗仍不确定，因此许多科学努力都集中在发现抗病毒治疗方法上。许多药物正在被研究以抑制冠状病毒主蛋白酶 3CLpro 切割其病毒多蛋白，但很少有文献涉及该蛋白酶与宿主蛋白质组的相互作用及其对毒力的可能贡献。由于实验验证的宿主蛋白裂解太少，因此无法完全了解 3CLpro 对相关细胞途径和组织的全局影响。在这里，我着手确定该蛋白酶的靶标及其相应的潜在药物靶标。我使用经过训练的神经网络来预测蛋白酶的目标和潜在的药物靶标，该神经网络基于 392 种冠状病毒蛋白质组中的裂解进行训练，马修斯相关系数为 0.985。我预测，人类蛋白质组的很大一部分容易受到 3CLpro 的影响，大约 20000 个人类蛋白中有 4898 个蛋白至少含有一个潜在的裂解位点。这些裂解是非随机分布的，并且在呼吸道、大脑、睾丸、血浆和免疫组织中的上皮细胞中富集，而嗅觉和味觉受体中则耗尽，尽管 COVID-19 患者普遍存在嗅觉丧失和味觉丧失。受影响的细胞途径包括细胞骨架/运动/细胞黏附蛋白、核浓缩和其他表观遗传学、宿主转录和 RNAi、核糖体化学计量和新生链检测和降解、泛素化、模式识别受体、凝血、脂蛋白、氧化还原和细胞凋亡。这种全蛋白质组裂解预测表明 3CLpro 在预期和影响毒力的重要非平凡途径中的重要性，促使我提出了十几个针对冠状病毒的潜在治疗靶标，因此应该应用于所有病毒蛋白酶，并随后进行实验验证。
