A new generation Mpro inhibitor with potent activity against SARS-CoV-2 Omicron variants

Abstract

Emerging SARS-CoV-2 variants, particularly the Omicron variant and its sublineages, continually threaten the global public health. Small molecule antivirals are an effective treatment strategy to fight against the virus. However, the first-generation antivirals either show limited clinical efficacy and/or have some defects in pharmacokinetic (PK) properties. Moreover, with increased use of these drugs across the globe, they face great pressure of drug resistance. We herein present the discovery and characterization of a new generation antiviral drug candidate (SY110), which is a potent and selective inhibitor of SARS-CoV-2 main protease (Mpro). This compound displayed potent in vitro antiviral activity against not only the predominant SARS-CoV-2 Omicron sublineage BA.5, but also other highly pathogenic human coronaviruses including SARS-CoV-1 and MERS-CoV. In the Omicron-infected K18-hACE2 mouse model, oral treatment with SY110 significantly lowered the viral burdens in lung and alleviated the virus-induced pathology. Importantly, SY110 possesses favorable PK properties with high oral drug exposure and oral bioavailability, and also an outstanding safety profile. Furthermore, SY110 exhibited sensitivity to several drug-resistance Mpro mutations. Collectively, this investigation provides a promising new drug candidate against Omicron and other variants of SARS-CoV-2.

Discovery of Nirmatrelvir Resistance Mutations in SARS-CoV-2 3CLpro: A Computational-Experimental Approach

“…SARS-CoV-2 replicons allow for the evaluation of nirmatrelvir resistance without conducting heavily regulated gain-of-function experiments using the infectious virus. The replicon systems provide a biologically safe alternative to infectious SARS-CoV-2 that recapitulate a large part of the viral replication cycle. , Consistent with previous studies, , nirmatrelvir remained effective at neutralizing omicron BA.1 with an EC 50 of 0.11 ± 0.02 μM (Table ). In comparison, our 3CLpro mutant discovered using FEP, S144A/E166A, constructed in the omicron BA.1 replicon, had an EC 50 of 2.22 ± 0.41 μM (Table ), indicating ∼20-fold resistance to nirmatrelvir in agreement with our IC 50 experiments (Figure a).…”

Strigolactones as Broad-Spectrum Antivirals against β-Coronaviruses through Targeting the Main Protease Mpro

“…These findings align with the observation that M pro is currently one of the primary targets of several antivirals, including Nirmatrelvir (the active component of Paxlovid), Ensitrelvir, and Simnotrelvir, which have already received clinical approval in certain countries and regions worldwide. Moreover, M pro is a promising target also considering the SL mechanism of action.…”

Data Driven Computational Design and Experimental Validation of Drugs for Accelerated Mitigation of Pandemic-like Scenarios

“…In their work, they focused on specific regions of the parent drug to design new functionalized drugs. However, their initial two attempts achieved limited success due to trial-and-error methods . These challenges emphasize the need for fast, target-specific drug design to tackle similar pandemic-like scenarios in the future.…”

“…30,31 A recent study by Huang et al experimentally showcased the potential of functionalizing existing compounds to obtain a new-generation selective inhibitor for M pro . 32 In their work, they focused on specific regions of the parent drug to design new functionalized drugs. However, their initial two attempts achieved limited success due to trial-and-error methods.…”

“…However, their initial two attempts achieved limited success due to trial-and-error methods. 32 These challenges emphasize the need for fast, target-specific drug design to tackle similar pandemic-like scenarios in the future. Computational screening of existing small-molecule inhibitors, coupled with the data-driven optimization of its functionalization strategies, can enable a faster and more extensive exploration of potential inhibitors for target specific action.…”