International Journal of Molecular Medical Science, 2024, Vol.14, No.1, 56-60 http://medscipublisher.com/index.php/ijmms 56 Scientific Review Open Access Innovative Antiviral Strategy Targeting PLpro: Discovery of Jun12682 and Analysis of Its Antipandemic Effects JiaXuan Tropical Veterinary Medicine Center, Hainan Institute of Tropical Agricultural Resources, Sanya, 572024, China Corresponding author email: cherryjxuan@gmail.com International Journal of Molecular Medical Science, 2024, Vol.14, No.1 doi: 10.5376/ijmms.2024.14.0008 Received: 29 Mar., 2024 Accepted: 03 Apr., 2024 Published: 09 Apr., 2024 Copyright © 2024 Xuan, This is an open access article published under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Preferred citation for this article: Xuan J., 2024, Innovative antiviral strategy targeting PLpro: Discovery of Jun12682 and analysis of its antipandemic effects, International Journal of Molecular Medical Science, 14(1): 56-60 (doi: 10.5376/ijmms.2024.14.0008) The paper "Design of a SARS-CoV-2 papain-like protease inhibitor with antiviral efficacy in a mouse model," authored by Bin Tan, Xiaoming Zhang, Ahmadullah Ansari, Prakash Jadhav, et al., was published in Science on March 29, 2024. The authors are affiliated with Department of Medicinal Chemistry, Ernest Mario School of Pharmacy, Rutgers, the State University of New Jersey, and Department of Physiological Sciences, College of Veterinary Medicine, Oklahoma State University, among others. This research focuses on a key enzyme of SARS-CoV-2, the papain-like protease (PLpro), which plays a crucial role in the virus's replication and immune evasion mechanisms. Using a structure-guided approach, the research team designed a series of non-covalent PLpro inhibitors. These inhibitors specifically target a newly discovered ubiquitin-binding site, Val70Ub, on PLpro, demonstrating their antiviral activity in both in vitro and in vivo models. The lead compound, Jun12682, showed excellent antiviral effects in a mouse model, improving survival rates, and reducing pulmonary viral loads, offering a new strategic direction for the treatment of SARS-CoV-2. 1 Experimental Data Analysis In the study, the discovery and evaluation of Jun12682 were accomplished through a series of meticulous experimental steps. In vitro experiments demonstrated that Jun12682 has very strong inhibitory activity against PLpro, with an inhibitory constant (Ki) of only 37.7 nanomolar, and an effective concentration for 50% of maximal effect (EC50) value of 1.1 micromolar in the FlipGFP PLpro cell assay, indicating its high efficacy in inhibiting the key enzyme activity of the virus. Further in vivo experiments conducted in a mouse model showed that Jun12682 significantly improved the survival rate of mice infected with SARS-CoV-2, mitigated the virus-induced weight loss, and effectively reduced the viral load in the lungs. These experimental data collectively validate the value of Jun12682 as a potential anti-SARS-CoV-2 therapeutic drug. Figure 1 displays the X-ray crystal structure of the hybrid covalent inhibitor Jun11313, designed based on XR8-24 and Cp7, with SARS-CoV-2 PLpro. In structure (B), the interactions between Jun11313 and the PLpro binding site are represented by hydrogen bonds (black dashed lines), with the spatial structure of Jun11313 shown in green ball-and-stick model. Figure (C) overlays the structure of PLpro with Jun11313 against the XR8-24 complex, highlighting the amino acid residues related to the binding of both compounds. Structure (D) further presents an overlay of the binding modes of Jun11313, XR8-24, and ubiquitin on PLpro. Structure (E) provides the generic chemical structure of the designed biarylphenyl PLpro inhibitors and highlights key interactions. Lastly, the flowchart (F) shows the optimization process for PLpro inhibitors, with Jun12682 being selected as the leading candidate for in vivo studies. Figure 2 showcases a series of representative compounds of biarylbenzamide class SARS-CoV-2 PLpro inhibitors. Item A in the illustration represents the positive control GRL0617; items B, C to F are PLpro inhibitors containing thiophene and pyrazole. These compounds were characterized for their half-maximal inhibitory concentration (IC50) and inhibitory constant (Ki) through FRET-based enzymatic activity assays, and their cytotoxicity (CC50)
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