tetano
Editor, Senior Moderator
J Med Chem
. 2023 Jul 20.
doi: 10.1021/acs.jmedchem.3c00576. Online ahead of print. C-2 Thiophenyl Tryptophan Trimers Inhibit Cellular Entry of SARS-CoV-2 through Interaction with the Viral Spike (S) Protein
Marta Gargantilla[SUP] 1 [/SUP], Clara Francés[SUP] 2 [/SUP], Anmol Adhav[SUP] 3 [/SUP], Alicia Forcada-Nadal[SUP] 3 4 [/SUP], Belén Martínez-Gualda[SUP] 1 [/SUP], Olaia Martí-Marí[SUP] 1 [/SUP], María Luisa López-Redondo[SUP] 3 [/SUP], Roberto Melero[SUP] 5 [/SUP], Clara Marco-Marín[SUP] 3 4 [/SUP], Nadine Gougeard[SUP] 3 4 [/SUP], Carolina Espinosa[SUP] 3 [/SUP], Antonio Rubio-Del-Campo[SUP] 3 [/SUP], Rafael Ruiz-Partida[SUP] 3 [/SUP], María Del Pilar Hernández-Sierra[SUP] 3 [/SUP], Laura Villamayor-Belinchón[SUP] 3 [/SUP], Jerónimo Bravo[SUP] 3 [/SUP], José-Luis Llacer[SUP] 3 4 [/SUP], Alberto Marina[SUP] 3 4 [/SUP], Vicente Rubio[SUP] 3 4 [/SUP], Ana San-Félix[SUP] 1 [/SUP], Ron Geller[SUP] 2 [/SUP], María-Jesús Pérez-Pérez[SUP] 1 [/SUP]
Affiliations
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.
. 2023 Jul 20.
doi: 10.1021/acs.jmedchem.3c00576. Online ahead of print. C-2 Thiophenyl Tryptophan Trimers Inhibit Cellular Entry of SARS-CoV-2 through Interaction with the Viral Spike (S) Protein
Marta Gargantilla[SUP] 1 [/SUP], Clara Francés[SUP] 2 [/SUP], Anmol Adhav[SUP] 3 [/SUP], Alicia Forcada-Nadal[SUP] 3 4 [/SUP], Belén Martínez-Gualda[SUP] 1 [/SUP], Olaia Martí-Marí[SUP] 1 [/SUP], María Luisa López-Redondo[SUP] 3 [/SUP], Roberto Melero[SUP] 5 [/SUP], Clara Marco-Marín[SUP] 3 4 [/SUP], Nadine Gougeard[SUP] 3 4 [/SUP], Carolina Espinosa[SUP] 3 [/SUP], Antonio Rubio-Del-Campo[SUP] 3 [/SUP], Rafael Ruiz-Partida[SUP] 3 [/SUP], María Del Pilar Hernández-Sierra[SUP] 3 [/SUP], Laura Villamayor-Belinchón[SUP] 3 [/SUP], Jerónimo Bravo[SUP] 3 [/SUP], José-Luis Llacer[SUP] 3 4 [/SUP], Alberto Marina[SUP] 3 4 [/SUP], Vicente Rubio[SUP] 3 4 [/SUP], Ana San-Félix[SUP] 1 [/SUP], Ron Geller[SUP] 2 [/SUP], María-Jesús Pérez-Pérez[SUP] 1 [/SUP]
Affiliations
- PMID: 37471688
- DOI: 10.1021/acs.jmedchem.3c00576
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.