Diastereomeric Resolution Yields Highly Potent Inhibitor of SARS-CoV-2 Main Protease.

SARS-CoV-2 is the causative agent behind the COVID-19 pandemic. The main protease (Mpro, 3CLpro) of SARS-CoV-2 is a key enzyme that processes polyproteins translated from the viral RNA. Mpro is therefore an attractive target for the design of inhibitors that block viral replication. We report the diastereomeric resolution of the previously designed SARS-CoV-2 Mpro α-ketoamide inhibitor 13b. The pure (S,S,S)-diastereomer, 13b-K, displays an IC50 of 120 nM against the Mpro and EC50 values of 0.8-3.4 µM for antiviral activity in different cell types. Crystal structures have been elucidated for the Mpro complexes with each of the major diastereomers, the active (S,S,S)-13b (13b-K), and the nearly inactive (R,S,S)-13b (13b-H); results for the latter reveal a novel binding mode. Pharmacokinetic studies show good levels of 13b-K after inhalative as well as after peroral administration. The active inhibitor (13b-K) is a promising candidate for further development as an antiviral treatment for COVID-19.

From Repurposing to Redesign: Optimization of Boceprevir to Highly Potent Inhibitors of the SARS-CoV-2 Main Protease.

The main protease (Mpro) of the betacoronavirus SARS-CoV-2 is an attractive target for the development of treatments for COVID-19. Structure-based design is a successful approach to discovering new inhibitors of the Mpro. Starting from crystal structures of the Mpro in complexes with the Hepatitis C virus NS3/4A protease inhibitors boceprevir and telaprevir, we optimized the potency of the alpha-ketoamide boceprevir against the Mpro by replacing its P1 cyclobutyl moiety by a γ-lactam as a glutamine surrogate. The resulting compound, MG-78, exhibited an IC50 of 13 nM versus the recombinant Mpro, and similar potency was observed for its P1' N-methyl derivative MG-131. Crystal structures confirmed the validity of our design concept. In addition to SARS-CoV-2 Mpro inhibition, we also explored the activity of MG-78 against the Mpro of the alphacoronavirus HCoV NL63 and against enterovirus 3C proteases. The activities were good (0.33 µM, HCoV-NL63 Mpro), moderate (1.45 µM, Coxsackievirus 3Cpro), and relatively poor (6.7 µM, enterovirus A71 3Cpro), respectively. The structural basis for the differences in activities was revealed by X-ray crystallo-graphy. We conclude that the modified boceprevir scaffold is suitable for obtaining high-potency inhibitors of the coronavirus Mpros but further optimization would be needed to target enterovirus 3Cpros efficiently.

Shear-thinning property of liquid system in many-body dissipative particle dynamics model

Many scientific research papers report that jet-like flow during speech is a potent route for viral transmission in the COVID-19 pandemic. Droplet emission occurs during breaking, speaking, singing, coughing and sneezing, which could be affected by the shear-thinning rheology of the liquid. Here we test the viscosity of simple liquid system in many-body dissipative particle dynamics model under different driven forces, which illustrates that the simple liquid system interestingly has shear-thinning property. Based on this, we simulate the process of jet-like flow and capture the rupture of liquid cylinder and the process of drop generation, which implies the jet-induced liquid pinchoff and drop generation can be regulated by initial driven force and its temperature. The results show that larger pressure pulse could generate longer liquid cylinder and larger drops, as well as at lower force frequency. This work can provide an insight in liquid jet-like flow with shear-thining property and yield a better understanding of virus spreading via salivary droplets. [ FROM AUTHOR] Copyright of Modern Physics Letters B is the property of World Scientific Publishing Company and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full . (Copyright applies to all s.)

Evaporation of liquid nanofilms: A minireview Note: This paper is part of the special topic, Flow and the Virus

Evaporation of virus-loaded droplets and liquid nanofilms plays a significant role in the pandemic of COVID-19. The evaporation mechanism of liquid nanofilms has attracted much attention in recent decades. In this minireview, we first introduce the relationship between the evaporation process of liquid nanofilms and the pandemic of COVID-19. Then, we briefly provide the frontiers of liquid droplet/nanofilm evaporation on solid surfaces. In addition, we discuss the potential application of machine learning in liquid nanofilm evaporation studies, which is expected to be helpful to build up a more accurate molecular model and to investigate the evaporation mechanism of liquid nanofilms on solid surfaces.

Evaporation of liquid nanofilms: A minireview.

Evaporation of virus-loaded droplets and liquid nanofilms plays a significant role in the pandemic of COVID-19. The evaporation mechanism of liquid nanofilms has attracted much attention in recent decades. In this minireview, we first introduce the relationship between the evaporation process of liquid nanofilms and the pandemic of COVID-19. Then, we briefly provide the frontiers of liquid droplet/nanofilm evaporation on solid surfaces. In addition, we discuss the potential application of machine learning in liquid nanofilm evaporation studies, which is expected to be helpful to build up a more accurate molecular model and to investigate the evaporation mechanism of liquid nanofilms on solid surfaces.