Structure-guided design of potent and permeable inhibitors of MERS coronavirus 3CL protease that utilize a piperidine moiety as a novel design element

Abstract

There are currently no approved vaccines or small molecule therapeutics available for the prophylaxis or treatment of Middle East Respiratory Syndrome coronavirus (MERS-CoV) infections. MERS-CoV 3CL protease is essential for viral replication; consequently, it is an attractive target that provides a potentially effective means of developing small molecule therapeutics for combatting MERS-CoV. We describe herein the structure-guided design and evaluation of a novel class of inhibitors of MERS-CoV 3CL protease that embody a piperidine moiety as a design element that is well-suited to exploiting favorable subsite binding interactions to attain optimal pharmacological activity and PK properties. The mechanism of action of the compounds and the structural determinants associated with binding were illuminated using X-ray crystallography.

Recent discovery and development of inhibitors targeting coronaviruses

“…A dipeptidyl transition state 3CL pro inhibitor GC376 (71) (FRET) assay [115]. Another pyrrolidinone based peptide GC813 (72) as well as its derivatives 73-74 displayed inhibition for MERS-CoV with EC50 values of 0.5 mM, 0.5 mM, and 0.8 mM in cell culture [116]. Kenichi et al reported new non-peptide SARS-CoV 3CL pro inhibitors [117] by introducing decahydroisoquinoline at the S2 position by connecting the cyclohexyl group of the substrate-based inhibitor 75 (Fig.…”

“…Groutas et al reported the novel class of peptidomimetic MERS-CoV3CL pro inhibitors that embody a piperidine moiety [116]. These inhibitors were designed based on the dipeptidyl aldehyde bisulfite adduct inhibitor, designated GC376 (84, Fig.…”

Déjà vu: Stimulating open drug discovery for SARS-CoV-2

“…We aligned the crystal structures of M pro of SARS-CoV, MERS-CoV and SARS-CoV-2 to compare the structures and the residues of the catalytic site. The catalytic site for SARS-CoV and SARS-CoV-2 are the same: His41-Cys145 [52], whereas for MERS-Cov it is His41-Cys148 [52] (Fig. 2).…”

Molecular Characteristics, Functions, and Related Pathogenicity of MERS-CoV Proteins

“…PLpro is controlled by a wide range of components, mutations, and other effects. Antiviral drugs, such as PLpro inhibitors and 3CLpro inhibitors (Table 2), have been studied for their innate immunosuppression profiles [41,42]. Nsp5 is widely involved in virus-encoded polyproteins (ppla, pplab) and 16 nsps processing; therefore, nsp5 is essential and indispensable for virus survival.…”