C-2 Thiophenyl Tryptophan Trimers Inhibit Cellular Entry of SARS-CoV-2 through Interaction with the Viral Spike (S) Protein

  • J Med Chem. 2023 Aug 10;66(15):10432-10457. doi: 10.1021/acs.jmedchem.3c00576.
Marta Gargantilla  1 ,  Clara Francés  2 ,  Anmol Adhav  3 ,  Alicia Forcada-Nadal  3  4 ,  Belén Martínez-Gualda  1 ,  Olaia Martí-Marí  1 ,  María Luisa López-Redondo  3 ,  Roberto Melero  5 ,  Clara Marco-Marín  3  4 ,  Nadine Gougeard  3  4 ,  Carolina Espinosa  3 ,  Antonio Rubio-Del-Campo  3 ,  Rafael Ruiz-Partida  3 ,  María Del Pilar Hernández-Sierra  3 ,  Laura Villamayor-Belinchón  3 ,  Jerónimo Bravo  3 ,  José-Luis Llacer  3  4 ,  Alberto Marina  3  4 ,  Vicente Rubio  3  4 ,  Ana San-Félix  1 ,  Ron Geller  2 ,  María-Jesús Pérez-Pérez  1
Affiliations
  • 1. Instituto de Química Médica (IQM, CSIC), c/Juan de la Cierva 3, Madrid 28006, Spain.
  • 2. Institute for Integrative Systems Biology (I2SysBio), UV-CSIC, c/Catedrático Agustin Escardino, 9, Paterna 46980, Valencia, Spain.
  • 3. Instituto de Biomedicina de Valencia (IBV, CSIC), c/Jaime Roig 11, Valencia 46010, Spain.
  • 4. Group 739, Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER-ISCIII), Madrid 28049, Spain.
  • 5. Centro Nacional de Biotecnología (CNB, CSIC), c/Darwin 3, Madrid 28049, Spain.
PMID: 37471688 DOI: 10.1021/acs.jmedchem.3c00576
Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19, by infecting cells via the interaction of its spike protein (S) with the primary cell receptor angiotensin-converting enzyme (ACE2). To search for inhibitors of this key step in viral Infection, we screened an in-house library of multivalent tryptophan derivatives. Using VSV-S pseudoparticles, we identified compound 2 as a potent entry inhibitor lacking cellular toxicity. Chemical optimization of 2 rendered compounds 63 and 65, which also potently inhibited genuine SARS-CoV-2 cell entry. Thermofluor and microscale thermophoresis studies revealed their binding to S and to its isolated receptor binding domain (RBD), interfering with the interaction with ACE2. High-resolution cryoelectron microscopy structure of S, free or bound to 2, shed light on cell entry inhibition mechanisms by these compounds. Overall, this work identifies and characterizes a new class of SARS-CoV-2 entry inhibitors with clear potential for preventing and/or fighting COVID-19.

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