MPD2 for COVID-19

ABSTRACT The emergence of the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) has underscored the urgent need for novel antiviral strategies. One of the primary targets of interest is the SARS‐CoV‐2 main protease (Mpro), which plays a crucial role in viral replication. Building on our prior work involving machine learning (ML)‐based virtual screening for potential Mpro inhibitors, we sought to experimentally validate top‐ranked candidates. Microscale thermophoresis (MST) was used to assess the binding affinity, leading to the identification of three promising hits from a library of 180 compounds. Notably, one compound demonstrated high‐affinity binding to SARS‐CoV‐2 Mpro ( K d = 2.8 ± 0.9 µM). However, enzymatic assays revealed that none of the hit compounds inhibited the activity of the protease, suggesting a non‐competitive binding. Docking and molecular dynamics (MD) simulations allowed to identify an accessory site in which the compounds exhibited stable interactions. These findings suggest that the identified compounds may serve as a starting point for the rational design of degradation‐inducing strategies, such as proteolysis‐targeting chimeras (PROTACs), targeting SARS‐CoV‐2 Mpro, and highlight the value of integrating ML‐driven discovery with biophysical and computational validation in antiviral drug development.

Proteolysis-targeting chimera (PROTAC) technology has demonstrated remarkable progress in tumor therapy, attributed to its unique capability of catalytically degrading “undruggable” targets. In the context of the ongoing global health threat posed by the Coronavirus Disease 2019 (COVID-19) pandemic, the application scope of PROTAC technology has been gradually extended to the field of antiviral research. Unlike traditional small molecule inhibitors, PROTAC employs an “event-driven” mechanism to achieve ubiquitination-mediated degradation of target proteins. This approach holds great promise in addressing challenges such as drug resistance, targeting host-dependent factors, and high-mutagenic viral proteins. This article provides a comprehensive review of the application progress of PROTAC technology in antiviral therapy, with a particular emphasis on successful cases across a range of viral pathogens, including Hepatitis B Virus (HBV), Hepatitis C Virus (HCV), influenza virus, and Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Additionally, it delves into the challenges encountered in this field and ponders future development directions. Through the integration of the latest research findings, this article proposes a dual-target degradation strategy based on the host–pathogen interaction interface. These proposals aim to offer theoretical support for the clinical translation of antiviral PROTACs.