Investigating theobromine as a potential anti-human coronaviral agent

IF 1.9 4区 医学 Q4 IMMUNOLOGY Microbiology and Immunology Pub Date : 2023-07-06 DOI:10.1111/1348-0421.13086
Jiajing Li, Yining Wang, Sajjan Rajpoot, Marla Lavrijsen, Qiuwei Pan, Pengfei Li, Mirza S. Baig
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Abstract

Coronaviruses (CoVs) have long been known to infect humans, mainly alpha-CoV and beta-CoV. The vaccines developed for SARS-CoV-2 are likely not effective against other coronavirus species, whereas the risk of the emergence of new strains that may cause the next epidemic/pandemic is high. The development of antiviral drugs that are effective across different CoVs represents a viable strategy for improving pandemic preparedness. In this study, we aim to identify pan-coronaviral agents by targeting the conserved main protease (Mpro). For drug screening, the catalytic dyad of four human CoVs (HCoVs: SARS-CoV-2, and seasonal CoV NL63, OC43, and 229E) was targeted by molecular docking. The identified leading candidate theobromine, a xanthine derivative, was further tested in cell culture models of coronavirus infection. Theobromine binds strongly with the catalytic dyad (His41 and Cys144/145) of SARS-CoV-2 and HCoV-NL63 Mpro, mildly with HCoV-OC43, but not with HCoV-229E. However, theobromine only shows dose-dependent inhibition in Calu3 cells inoculated with SARS-CoV-2, but not in cells inoculated with seasonal CoVs. Theobromine exerts antiviral activity against coronavirus infections potentially through targeting Mpro. However, the antiviral potency is distinct among different CoVs.

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研究可可碱作为一种潜在的抗人类冠状病毒药物
人们早就知道冠状病毒(cov)会感染人类,主要是甲型冠状病毒和乙型冠状病毒。针对SARS-CoV-2开发的疫苗可能对其他冠状病毒物种无效,而出现可能导致下一次流行/大流行的新菌株的风险很高。开发对不同冠状病毒有效的抗病毒药物是改善大流行防范的一项可行战略。在这项研究中,我们的目标是通过靶向保守主蛋白酶(Mpro)来鉴定泛冠状病毒因子。为了进行药物筛选,我们通过分子对接的方法靶向了4种人类冠状病毒(hcov: SARS-CoV-2和季节性冠状病毒NL63、OC43和229E)的催化二联体。确定的主要候选可可碱是一种黄嘌呤衍生物,在冠状病毒感染的细胞培养模型中进行了进一步测试。可可碱与SARS-CoV-2和HCoV-NL63 Mpro的催化二联体(His41和Cys144/145)结合强烈,与HCoV-OC43结合轻微,但与HCoV-229E不结合。然而,可可碱仅在接种了SARS-CoV-2的Calu3细胞中表现出剂量依赖性抑制,而在接种了季节性cov的细胞中没有表现出剂量依赖性抑制。可可碱可能通过靶向Mpro对冠状病毒感染发挥抗病毒活性。然而,不同冠状病毒的抗病毒效力是不同的。
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来源期刊
Microbiology and Immunology
Microbiology and Immunology 医学-免疫学
CiteScore
5.20
自引率
3.80%
发文量
78
审稿时长
1 months
期刊介绍: Microbiology and Immunology is published in association with Japanese Society for Bacteriology, Japanese Society for Virology, and Japanese Society for Host Defense Research. It is peer-reviewed publication that provides insight into the study of microbes and the host immune, biological and physiological responses. Fields covered by Microbiology and Immunology include:Bacteriology|Virology|Immunology|pathogenic infections in human, animals and plants|pathogenicity and virulence factors such as microbial toxins and cell-surface components|factors involved in host defense, inflammation, development of vaccines|antimicrobial agents and drug resistance of microbes|genomics and proteomics.
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