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  2. Discovery of an ellipticine derivative as TLR3 inhibitor against influenza A virus and SARS-CoV-2

Discovery of an ellipticine derivative as TLR3 inhibitor against influenza A virus and SARS-CoV-2

  • Bioorg Med Chem Lett. 2024 Mar 15:101:129672. doi: 10.1016/j.bmcl.2024.129672.
Yue Pan 1 Qiuyue Fu 1 Yinyan Li 1 Jie Yang 2 Kui Cheng 3
Affiliations

Affiliations

  • 1 Guangdong Provincial Key Laboratory of New Drug Screening, NMPA Key Laboratory for Research and Evaluation of Drug Metabolism and Guangdong-Hong Kong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
  • 2 Guangdong Provincial Key Laboratory of New Drug Screening, NMPA Key Laboratory for Research and Evaluation of Drug Metabolism and Guangdong-Hong Kong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China. Electronic address: yj528@smu.edu.cn.
  • 3 Guangdong Provincial Key Laboratory of New Drug Screening, NMPA Key Laboratory for Research and Evaluation of Drug Metabolism and Guangdong-Hong Kong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China. Electronic address: chengk@smu.edu.cn.
Abstract

Influenza and COVID-19 continue to pose global threats to public health. Classic Antiviral drugs have certain limitations, coupled with frequent viral mutations leading to many drugs being ineffective, the development of new Antiviral drugs is urgent. Meanwhile, the invasion of Influenza Virus can cause an immune response, and an excessive immune response can generate a large number of inflammatory storms, leading to tissue damage. Toll-like Receptor 3 (TLR3) recognizes virus dsRNA to ignite the innate immune response, and inhibit TLR3 can block the excess immune response and protect the host tissues. Taking TLR3 as the target, SMU-CX1 was obtained as the specific TLR3 Inhibitor by high-throughput screening of 15,700 compounds with IC50 value of 0.11 µM. Its anti-influenza A virus activity with IC50 ranged from 0.14 to 0.33 µM against multiple subtypes of influenza A virus and also showed promising anti-SARS-CoV-2 activity with IC50 at 0.43 µM. Primary Antiviral mechanism study indicated that SMU-CX1 significantly inhibited PB2 and NP protein of viruses, it can also inhibit inflammatory factors in host cells including IFN-β, IP-10 and CCL-5. In conclusion, this study demonstrates the potential of SMU-CX1 in inhibiting IAV and SARS-CoV-2 activity, thereby offering a novel approach for designing Antiviral drugs against highly pathogenic viruses.

Keywords

Anti-inflammatory; Influenza A virus; SARS-CoV-2; Small molecule; Toll-like receptor 3.

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