Targeting SARS-CoV-2 entry processes: The promising potential and future of host-targeted small-molecule inhibitors

Eur J Med Chem. 2024 Jan 5:263:115923. doi: 10.1016/j.ejmech.2023.115923.

Aijia Wu ¹, Kunyu Shi ², Jiaxing Wang ³, Ruofei Zhang ¹, Yuxi Wang ⁴

Affiliations

1 Department of Pulmonary and Critical Care Medicine, Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, National Clinical Research Center for Geriatrics, Precision Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China; West China School of Pharmacy, Sichuan University, Chengdu, 610041, China.
2 Department of Pulmonary and Critical Care Medicine, Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, National Clinical Research Center for Geriatrics, Precision Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China; Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu, 610212, China.
3 Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, 38163, Tennessee, United States.
4 Department of Pulmonary and Critical Care Medicine, Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, National Clinical Research Center for Geriatrics, Precision Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China; Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu, 610212, China. Electronic address: [email protected].

PMID: 37981443 DOI: 10.1016/j.ejmech.2023.115923

Abstract

The COVID-19 pandemic, caused by SARS-CoV-2, has had a huge impact on global health. To respond to rapidly mutating viruses and to prepare for the next pandemic, there is an urgent need to develop small molecule therapies that target critical stages of the SARS-CoV-2 life cycle. Inhibiting the entry process of the virus can effectively control viral Infection and play a role in prevention and treatment. Host factors involved in this process, such as ACE2, TMPRSS2, ADAM17, Furin, PIKfyve, TPC2, CTSL, AAK1, V-ATPase, HSPG, and NRP1, have been found to be potentially good targets with stability. Through further exploration of the cell entry process of SARS-CoV-2, small-molecule drugs targeting these host factors have been developed. This review focuses on the structural functions of potential host cell targets during the entry of SARS-CoV-2 into host cells. The research progress, chemical structure, structure-activity relationship, and clinical value of small-molecule inhibitors against COVID-19 are reviewed to provide a reference for the development of small-molecule drugs against COVID-19.

Keywords

COVID-19; Drug design; Host-targeted; Small molecule inhibitors; Virus entry.

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