Deciphering COVID-19 host transcriptomic complexity and variations for therapeutic discovery against new variants
Jing Xing,
Rama Shankar,
Meehyun Ko,
Keke Zhang,
Sulin Zhang,
Aleksandra Drelich,
Shreya Paithankar,
Eugene Chekalin,
Mei-Sze Chua,
Surender Rajasekaran,
Chien-Te Kent Tseng,
Mingyue Zheng,
Seungtaek Kim,
Bin Chen
Affiliations
Jing Xing
Department of Pediatrics and Human Development, Michigan State University, Grand Rapids, MI 49503, USA
Rama Shankar
Department of Pediatrics and Human Development, Michigan State University, Grand Rapids, MI 49503, USA
Meehyun Ko
Zoonotic Virus Laboratory, Institut Pasteur Korea, Seongnam-si, Gyeonggi-do, 13488, Korea
Keke Zhang
Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
Sulin Zhang
Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
Aleksandra Drelich
Departments of Microbiology and Immunology, The University of Texas Medical Branch, Galveston, TX 77555, USA
Shreya Paithankar
Department of Pediatrics and Human Development, Michigan State University, Grand Rapids, MI 49503, USA
Eugene Chekalin
Department of Pediatrics and Human Development, Michigan State University, Grand Rapids, MI 49503, USA
Mei-Sze Chua
Department of Surgery, Stanford University School of Medicine, Palo Alto, CA, USA
Surender Rajasekaran
Department of Pediatrics and Human Development, Michigan State University, Grand Rapids, MI 49503, USA; Helen DeVos Children’s Hospital, Grand Rapids, MI 49503, USA
Chien-Te Kent Tseng
Departments of Microbiology and Immunology, The University of Texas Medical Branch, Galveston, TX 77555, USA; Center of Biodefense and Emerging Infectious Diseases, The University of Texas Medical Branch, Galveston, TX 77555, USA
Mingyue Zheng
Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
Department of Pediatrics and Human Development, Michigan State University, Grand Rapids, MI 49503, USA; Department of Pharmacology and Toxicology, Michigan State University, Grand Rapids, MI 49503, USA; Department of Computer Science and Engineering, Michigan State University, East Lansing, MI 48824, USA; Corresponding author
Summary: The molecular manifestations of host cells responding to SARS-CoV-2 and its evolving variants of infection are vastly different across the studied models and conditions, imposing challenges for host-based antiviral drug discovery. Based on the postulation that antiviral drugs tend to reverse the global host gene expression induced by viral infection, we retrospectively evaluated hundreds of signatures derived from 1,700 published host transcriptomic profiles of SARS/MERS/SARS-CoV-2 infection using an iterative data-driven approach. A few of these signatures could be reversed by known anti-SARS-CoV-2 inhibitors, suggesting the potential of extrapolating the biology for new variant research. We discovered IMD-0354 as a promising candidate to reverse the signatures globally with nanomolar IC50 against SARS-CoV-2 and its five variants. IMD-0354 stimulated type I interferon antiviral response, inhibited viral entry, and down-regulated hijacked proteins. This study demonstrates that the conserved coronavirus signatures and the transcriptomic reversal approach that leverages polypharmacological effects could guide new variant therapeutic discovery.
