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. 2024 Mar 15:268:116263.
doi: 10.1016/j.ejmech.2024.116263. Epub 2024 Feb 24.

Synthesis and biological evaluation of novel peptidomimetic inhibitors of the coronavirus 3C-like protease

Franck Amblard  1 , Julia C LeCher  2 , Ramyani De  2 , Shaoman Zhou  2 , Peng Liu  2 , Shu Ling Goh  2 , Sijia Tao  2 , Dharmeshkumar Patel  2 , Jessica Downs-Bowen  2 , Keivan Zandi  2 , Huanchun Zhang  2 , Gitika Chaudhry  2 , Tamara McBrayer  2 , Michael Muczynski  3 , Abdullah Al-Homoudi  3 , Joseph Engel  3 , Shuiyun Lan  2 , Stefan G Sarafianos  2 , Ladislau C Kovari  3 , Raymond F Schinazi  4
Affiliations

Synthesis and biological evaluation of novel peptidomimetic inhibitors of the coronavirus 3C-like protease

Franck Amblard et al. Eur J Med Chem. .

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and related variants, are responsible for the devastating coronavirus disease 2019 (COVID-19) pandemic. The SARS-CoV-2 main protease (Mpro) plays a central role in the replication of the virus and represents an attractive drug target. Herein, we report the discovery of novel SARS-CoV-2 Mpro covalent inhibitors, including highly effective compound NIP-22c which displays high potency against several key variants and clinically relevant nirmatrelvir Mpro E166V mutants.

Keywords: 3CL(pro); Antivirals; HCoV-OC43; Main protease; Mpro; NIP-22c; Peptides; SARS-CoV-2.

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Conflict of interest statement

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Raymond Schinazi reports financial support was provided by National Institutes of Health. Ladislau Kovari reports financial support was provided by National Institutes of Health. Ladislau Kovari reports financial support was provided National Institutes of Health and by Richard Barber Interdisciplinary Program grant. Stefan Sarafianos reports financial support was provided National Institutes of Health and by Nahmias-Schinazi Distinguished Research Chair. R. Schinazi, K. Zandi, F. Amblard has patent Peptidomimetics for the treatment of coronavirus and picornavirus infections issued to Emory university. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Figure 1:
Figure 1:
Examples of known SARS-CoV-2 3CLpro inhibitors
Figure 2:
Figure 2:
Structures of the peptidomimetics synthesized and evaluated for antiviral activity.
Figure 3:
Figure 3:
Covalent docking of NIP-22c in the active site of the crystal structure of the SARS-CoV-2 3CLpro (6Y2G.pdb).
Figure 4:
Figure 4:
A) Superimposition of the WT type (yellow) and mutant E166V (green) crystal structures of nirmatelvir-SARS-CoV-2 3CLpro complex B) Superimposition of docked NIP-22c with WT type (yellow) and mutant E166V (green) SARS-CoV-2 3CLpro complexes. The violet dashed line shows the distance between the closest atoms of the protein and the ligand.
Scheme 1.
Scheme 1.
Reagents and conditions: a) 1) 4 N HCl in dioxane, DCM, rt; 2) Boc-L-Leu-OH, HOBt, EDC.HCl, DIPEA, DCM, rt, overnight, 61%; b) 1) 4 N HCl in dioxane, DCM, rt; 2) Z-4-fluoro-L-phenylalanine, Z-3-(2-naphthyl)-L-alanine or Z-L-Tyrosine, HOBt, EDC.HCl, DIPEA, DCM, rt, overnight, 69% (R = F), 83% (R = naphthyl), 58% (R = OH); c) LiBH4/THF, 0 °C to rt, 2 hr, 80% (R = F), 53% (R = naphthyl), 73% (R = OH); d) for R = F: Dess-Martin periodinane, rt, 4 h, 57%； for R = naphthyl: Py.SO3/DIPEA DCM-DMSO, rt, 12 hr, 53%; for R = OH: Py.SO3/DIPEA DCM-DMSO, rt, 12 hr, 56%.
Scheme 2.
Scheme 2.
Reagents and conditions: a) 1N LiOH, THF, rt, 84%; b) NH4OH, HOBt, EDC, DCM/DMF, rt, 16 h, 52%; c) i) 4 N HCl in dioxane, DCM, rt, 2 hr; ii) N-Boc-L-Leu-OH, HOBt, EDC.HCl, DIPEA, DCM, rt, overnight, 62%; d) i) 4 N HCl in dioxane, DCM, rt, 2 hr; ii) N-Z-3-(2-naphthyl)-L-alanine, HOBt, EDC.HCl, DIPEA, DCM, rt, overnight, 61%; e) (CF3CO)2O, Et3N, THF, 0°C to rt, 3 h, 61%.
Scheme 3.
Scheme 3.
Reagents and conditions: a) 2-cyanoacetamide, piperidine, EtOH, 80 °C, 35 min, 36%;
Scheme 4.
Scheme 4.
Reagents and conditions: a) H-L-Leu-OMe·HCl, HOBt, EDC.HCl, DIPEA, DCM, rt, 52%; b) LiOH, THF-H2O, rt, 2 hr, 95%; c) 1) NHBoc-CH(CH2R2)-COOMeTFA/DCM, HOBt, EDC.HCl, DIPEA, DCM, rt.; d) LiBH4, THF; e) Py.SO3·, DIPEA, DCM-DMSO, rt.
Scheme 5.
Scheme 5.
Reagents and conditions: a) 1) 4 N HCl in dioxane, DCM, rt; 2) N-Boc-3-(2-naphthyl)-L-alanine, HOBt, EDC.HCl, DIPEA, DCM, rt, overnight, 74%; b) 4 N HCl in dioxane, DCM, rt; c) R1-COOH, HOBt, EDC.HCl, DIPEA, DCM, rt, overnight, 62–75%; d) NaBH4, MeOH, 0 °C to rt, 2 hr, 62–85%; e) Dess-Martin periodinane, rt, 1 h, 55–64%.
Scheme 6.
Scheme 6.
Reagents and conditions: a) For 23a: triethyl phosphonoacetate, NaH, THF, −78°C to −30°C, 1 h, 58%; For 23b: 1) acetic anhydride, isocyanocyclopropane, AcOEt, rt, 3 hr, 68%; 2) 1N LiOH, THF, rt, 1 hr, 70%; For 23c: NaHSO3, AcOEt/EtOH/H2O, 60°C, 4 h, 57%.
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