Design, Synthesis, and Biological Evaluation of Peptidomimetic Aldehydes as Broad-Spectrum Inhibitors against Enterovirus and SARS-CoV-2

Abstract

A novel series of peptidomimetic aldehydes was designed and synthesized to target 3C protease (3Cpro) of enterovirus 71 (EV71). Most of the compounds exhibited high antiviral activity, and among them, compound 18p demonstrated potent enzyme inhibitory activity and broad-spectrum antiviral activity on a panel of enteroviruses and rhinoviruses. The crystal structure of EV71 3Cpro in complex with 18p determined at a resolution of 1.2 Å revealed that 18p covalently linked to the catalytic Cys147 with an aldehyde group. In addition, these compounds also exhibited good inhibitory activity against the 3CLpro and the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), especially compound 18p (IC50 = 0.034 μM, EC50 = 0.29 μM). According to our previous work, these compounds have no reasons for concern regarding acute toxicity. Compared with AG7088, compound 18p also exhibited good pharmacokinetic properties and more potent anticoronavirus activity, making it an excellent lead for further development.

A Review of the Current Landscape of SARS-CoV-2 Main Protease Inhibitors: Have We Hit the Bullseye Yet?

“…Figure 6 compares the pIC 50 values of some SARS-CoV-2 M-pro inhibitors with their anti SARS-CoV-2 activities, measured as pEC 50 values. To avoid comparisons between values from different laboratories, data from five articles [ 49 , 59 , 69 , 99 , 100 ] that calculate the pIC 50 and pEC 50 for a set of compounds are shown independently. In all but one case, the pEC 50 values are lower than the pIC 50 values, showing that the potency of a compound to inhibit SARS-CoV-2 replication in cells cannot always be inferred from the potency to inhibit the M-pro determined in vitro.…”

The N-Terminal Carbamate is Key to High Cellular and Antiviral Potency for Boceprevir-Based SARS-CoV-2 Main Protease Inhibitors

“…Past efforts in developing M Pro inhibitors have been either using a P1 b-(S-2oxopyrrolidin-3yl)-alanyl (opal) residue in a peptidyl inhibitor or a pyridine moiety to engage the P1 binding pocket of M Pro for strong binding. 6,8,15,[23][24][25][26][27][28][29][30] Boceprevir has a P1 b-cyclobutylalanyl moiety that displays loose binding to the M Pro P1 binding pocket in its M Pro complex structure, 14-16, 19, 20 which explains its relatively moderate M Pro inhibition potency. In our designed boceprevir derivatives, this site is replaced by opal.…”

A Patent Review on SARS Coronavirus Main Protease (3CLpro) Inhibitors

“…This distinction is an important consideration when designing new coronavirus 3CL pro inhibitors and may be the reason why a P2 leucine was selected for Pfizer's lead compound PF-00835231 (Figure 6b). [18] 18 b was also reported to be the most potent SARS-CoV-2 3CL pro inhibitor (IC 50 34 nM) amongst 13 peptide aldehydes in a recent publication, [68] suggesting that inhibitors designed for SARS-CoV 3CL pro can be effectively used to inhibit SARS-CoV-2 3CL pro . Interestingly, the addition of a P3 valine to 18 b to yield tripeptide aldehyde 18 d resulted in an approximate 2-fold activity reduction for SARS-CoV and SARS-CoV-2 3CL pro (IC 50 s 30 to 50 nM and 34 to 68 nM respectively).…”

“…Interestingly, the addition of a P3 valine to 18 b to yield tripeptide aldehyde 18 d resulted in an approximate 2-fold activity reduction for SARS-CoV and SARS-CoV-2 3CL pro (IC 50 s 30 to 50 nM and 34 to 68 nM respectively). [68] Notably, all the inhibitors described in the patent possess highly electrophilic aldehyde warheads which are known to be highly reactive towards endogenous biological nucleophiles, potentially rendering them cytotoxic. Aldehydes are also metabolically unstable due to their susceptibility to oxidation and reduction by liver enzymes.…”