The synthesis of α-fluorinated methyl ketones has always been challenging. New methods based on the homologation chemistry via nucleophilic halocarbenoid transfer, carried out recently in our labs, allowed us to design and synthesize a target-directed dipeptidyl α,α-difluoromethyl ketone (DFMK) 8 as a potential antiviral agent with activity against human coronaviruses. The abil-ity of the newly synthesized compound to inhibit viral replication was evaluated by a viral cyto-pathic effect (CPE)-based assay performed on MCR5 cells infected with one of the four human coro-naviruses associated with respiratory distress, i.e., hCoV-229E, showing antiproliferative activity in the micromolar range (EC50 = 12.9 ± 1.22 µM), with a very low cytotoxicity profile (CC50 = 170 ± 3.79 µM, 307 ± 11.63 µM, and 174 ± 7.6 µM for A549, human embryonic lung fibroblasts (HELFs), and MRC5 cells, respectively). Docking and molecular dynamics simulations studies indicated that 8 efficaciously binds to the intended target hCoV-229E main protease (Mpro). Moreover, due to the high similarity between hCoV-229E Mpro and SARS-CoV-2 Mpro, we also performed the in silico analysis towards the second target, which showed results comparable to those obtained for hCoV-229E Mpro and promising in terms of energy of binding and docking pose.

Pseudo-dipeptide bearing α,α-difluoromethyl ketone moiety as electrophilic warhead with activity against coronaviruses

Mognetti B.;Gribaudo G.;Pace V.;
2021

Abstract

The synthesis of α-fluorinated methyl ketones has always been challenging. New methods based on the homologation chemistry via nucleophilic halocarbenoid transfer, carried out recently in our labs, allowed us to design and synthesize a target-directed dipeptidyl α,α-difluoromethyl ketone (DFMK) 8 as a potential antiviral agent with activity against human coronaviruses. The abil-ity of the newly synthesized compound to inhibit viral replication was evaluated by a viral cyto-pathic effect (CPE)-based assay performed on MCR5 cells infected with one of the four human coro-naviruses associated with respiratory distress, i.e., hCoV-229E, showing antiproliferative activity in the micromolar range (EC50 = 12.9 ± 1.22 µM), with a very low cytotoxicity profile (CC50 = 170 ± 3.79 µM, 307 ± 11.63 µM, and 174 ± 7.6 µM for A549, human embryonic lung fibroblasts (HELFs), and MRC5 cells, respectively). Docking and molecular dynamics simulations studies indicated that 8 efficaciously binds to the intended target hCoV-229E main protease (Mpro). Moreover, due to the high similarity between hCoV-229E Mpro and SARS-CoV-2 Mpro, we also performed the in silico analysis towards the second target, which showed results comparable to those obtained for hCoV-229E Mpro and promising in terms of energy of binding and docking pose.
22
3
1
17
Coronavirus; Cysteine proteases; Difluoromethyl ketone; HCoV-229E; SARS-CoV-2 M; pro
Citarella A.; Gentile D.; Rescifina A.; Piperno A.; Mognetti B.; Gribaudo G.; Sciortino M.T.; Holzer W.; Pace V.; Micale N.
File in questo prodotto:
File Dimensione Formato  
Citarella et al.,_IJMS_2021.pdf

accesso aperto

Tipo di file: PDF EDITORIALE
Dimensione 3.19 MB
Formato Adobe PDF
3.19 MB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2318/1772917
Citazioni
  • ???jsp.display-item.citation.pmc??? 4
  • Scopus 7
  • ???jsp.display-item.citation.isi??? 6
social impact