2. Academic Validation
  3. Computational and Experimental Approaches Identify Beta-Blockers as Potential SARS-CoV-2 Spike Inhibitors

Computational and Experimental Approaches Identify Beta-Blockers as Potential SARS-CoV-2 Spike Inhibitors

  • ACS Omega. 2022 Aug 8;7(32):27950-27958. doi: 10.1021/acsomega.2c01707.
Ana C Puhl 1,  Melina Mottin 2 3,  Carolina Q Sacramento 4 5,  Tatyana Almeida Tavella 6,  Gabriel Gonçalves Dias 2,  Natalia Fintelman-Rodrigues 4 5,  Jairo R Temerozo 7 8,  Suelen S G Dias 4,  Paulo Ricardo Pimenta da Silva Ramos 2,  Eric M Merten 9,  Kenneth H Pearce 9 10,  Fabio Trindade Maranhão Costa 6,  Lakshmanane Premkumar 11,  Thiago Moreno L Souza 4 5,  Carolina Horta Andrade 2,  Sean Ekins 1
Affiliations

Affiliations

  • 1 Collaborations Pharmaceuticals, Inc., 840 Main Campus Drive, Lab 3510, Raleigh, North Carolina 27606, United States.
  • 2 LabMol - Laboratory of Molecular Modeling and Drug Design, Faculdade de Farmácia, Universidade Federal de Goiás, Goiânia 74605-170, GO, Brazil.
  • 3 Pathogen-Host Interface Laboratory, Department of Cell Biology, University of Brasilia, Brasilia 70910-900, Brazil.
  • 4 Laboratory of Immunopharmacology, Oswaldo Cruz Institute-Fiocruz, Rio de Janeiro 21040-360, RJ, Brazil.
  • 5 Center of Technological Development in Health (CDTS)/National Institute of Science and Technology for Innovation on Neglected Population Diseases (INCT-IDPN), Rio de Janeiro 21040-900, RJ, Brazil.
  • 6 Laboratory of Tropical Diseases-Prof. Dr. Luiz Jacinto da Silva, Department of Genetics, Evolution, Microbiology and Immunology, University of Campinas-UNICAMP, Campinas 13083-970, SP, Brazil.
  • 7 Laboratory on Thymus Research, Oswaldo Cruz Institute-Fiocruz, Rio de Janeiro 21040-900, RJ, Brazil.
  • 8 National Institute for Science and Technology on Neuroimmunomodulation (INCT/NIM), Oswaldo Cruz Institute-Fiocruz, Rio de Janeiro 21040-360, RJ, Brazil.
  • 9 Center for Integrative Chemical Biology and Drug Discovery, Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599, United States.
  • 10 UNC Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina 27599, United States.
  • 11 Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599, United States.
PMID: 35983371 DOI: 10.1021/acsomega.2c01707
Abstract

Finding antivirals for SARS-CoV-2 is still a major challenge, and many computational and experimental approaches have been employed to find a solution to this problem. While the global vaccination campaigns are the primary driver of controlling the current pandemic, orally bioavailable small-molecule drugs and biologics are critical to overcome this global issue. Improved therapeutics and prophylactics are required to treat people with circulating and emerging new variants, addressing severe Infection, and people with underlying or immunocompromised conditions. The SARS-CoV-2 envelope spike is a challenging target for viral entry inhibitors. Pindolol presented a good docking score in a previous virtual screening using computational docking calculations after screening a Food and Drug Administration (FDA)-approved drug library of 2400 molecules as potential candidates to block the SARS-CoV-2 spike protein interaction with the angiotensin-converting enzyme 2 (ACE-2). Here, we expanded the computational evaluation to identify five beta-blockers against SARS-CoV-2 using several techniques, such as microscale thermophoresis, NanoDSF, and in vitro assays in different cell lines. These data identified carvedilol with a K d of 364 ± 22 nM for the SARS-CoV-2 spike and in vitro activity (EC50 of 7.57 μM, CC50 of 18.07 μM) against SARS-CoV-2 in Calu-3 cells. We have shown how we can apply multiple computational and experimental approaches to find molecules that can be further optimized to improve anti-SARS-CoV-2 activity.

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