Why is the Omicron main protease of SARS-CoV-2 less stable than its wild-type counterpart? A crystallographic, biophysical, and theoretical study DOI Creative Commons
Mohamed Ibrahim, Xinyuanyuan Sun, Vinícius M. de Oliveira

et al.

hLife, Journal Year: 2024, Volume and Issue: 2(8), P. 419 - 433

Published: June 15, 2024

During the continuing evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Omicron variant concern emerged in second half 2021 and has been dominant since November that year. Along with its sublineages, it maintained a prominent role ever since. The Nsp5 main protease (Mpro) virus is characterized by single mutation, P132H. Here we determined X-ray crystal structures P132H mutant (or O-Mpro) as free enzyme complex Mpro inhibitor, alpha-ketoamide 13b-K, conducted enzymological, biophysical well theoretical studies to characterize O-Mpro. We found O-Mpro similar overall structure binding 13b-K; however, displays lower enzymatic activity thermal stability compared WT-Mpro (with "WT" referring prototype strain). Intriguingly, imidazole ring His132 carboxylate plane Glu240 are stacked configuration here. Empirical folding energy calculations suggest dimer destabilized relative due less favorable van der Waals interactions backbone conformations individual protomers. All-atom continuous constant-pH molecular dynamics (MD) simulations reveal display coupled titration. At pH 7, predominantly neutral respect which charged. In order examine whether mutation eases emergence further mutations, also analyzed P132H+T169S double mutant, characteristic BA.1.1.2 lineage. However, little evidence correlation between two sites.

Language: Английский

SARS-CoV-2 Drug Resistance and Therapeutic Approaches DOI Creative Commons

Sania Batool,

Santosh Chokkakula, Ju Hwan Jeong

et al.

Heliyon, Journal Year: 2025, Volume and Issue: 11(2), P. e41980 - e41980

Published: Jan. 1, 2025

Language: Английский

Citations

4
SARS-CoV-2 resistance to monoclonal antibodies and small-molecule drugs DOI Creative Commons
Sho Iketani, David D. Ho

Cell chemical biology, Journal Year: 2024, Volume and Issue: 31(4), P. 632 - 657

Published: April 1, 2024

Over four years have passed since the beginning of COVID-19 pandemic. The scientific response has been rapid and effective, with many therapeutic monoclonal antibodies small molecules developed for clinical use. However, given ability viruses to become resistant antivirals, it is perhaps no surprise that field identified resistance nearly all these compounds. Here, we provide a comprehensive review profile each therapeutics. We hope this resource provides an atlas mutations be aware agent, particularly as springboard considerations next generation antivirals. Finally, discuss outlook thoughts moving forward in how continue manage this, next,

Language: Английский

Citations

14
Ensitrelvir Fumaric Acid: First Approval DOI

Yahiya Y. Syed

Drugs, Journal Year: 2024, Volume and Issue: 84(6), P. 721 - 728

Published: May 25, 2024

Language: Английский

Citations

10
Non-peptidic inhibitors targeting SARS-CoV-2 main protease: A review DOI

Ya-Qi Xiao,

Jiao Long, Shuang‐Shuang Zhang

et al.

Bioorganic Chemistry, Journal Year: 2024, Volume and Issue: 147, P. 107380 - 107380

Published: April 16, 2024

Language: Английский

Citations

9
Ensitrelvir treatment-emergent amino acid substitutions in SARS-CoV-2 3CLpro detected in the SCORPIO-SR phase 3 trial DOI Creative Commons
Takeki Uehara, Hiroshi Yotsuyanagi, Norio Ohmagari

et al.

Antiviral Research, Journal Year: 2025, Volume and Issue: unknown, P. 106097 - 106097

Published: Jan. 1, 2025

Language: Английский

Citations

1
Computational evaluation and benchmark study of 342 crystallographic holo-structures of SARS-CoV-2 Mpro enzyme DOI Creative Commons
Hamlet Khachatryan, Mher Matevosyan,

Vardan Harutyunyan

et al.

Scientific Reports, Journal Year: 2024, Volume and Issue: 14(1)

Published: June 20, 2024

Abstract The coronavirus disease 19 pandemic, caused by severe acute respiratory syndrome 2 (SARS-CoV-2), has led to a global health crisis with millions of confirmed cases and related deaths. main protease (Mpro) SARS-CoV-2 is crucial for viral replication presents an attractive target drug development. Despite the approval some drugs, search effective treatments continues. In this study, we systematically evaluated 342 holo-crystal structures Mpro identify optimal conformations structure-based virtual screening (SBVS). Our analysis revealed limited structural flexibility among structures. Three docking programs, AutoDock Vina, rDock, Glide were employed assess efficiency screening, revealing diverse performances across selected We found that 5RHE, 7DDC, 7DPU (PDB Ids) consistently displayed lowest EF, AUC, BEDROCK scores. Furthermore, these demonstrated worst pose prediction results in all programs. Two differences contribute variations performance: absence S1 subsite 7DDC 7DPU, presence subpocket S2 5RHE. These findings underscore importance selecting appropriate SBVS, providing valuable insights advancing discovery efforts.

Language: Английский

Citations

6
Study of key residues in MERS-CoV and SARS-CoV-2 main proteases for resistance against clinically applied inhibitors nirmatrelvir and ensitrelvir DOI Creative Commons
Laura Krismer, Helge Schöppe, Stefanie Rauch

et al.

npj Viruses, Journal Year: 2024, Volume and Issue: 2(1)

Published: June 24, 2024

Abstract The Middle East Respiratory Syndrome Coronavirus (MERS-CoV) is an epidemic, zoonotically emerging pathogen initially reported in Saudi Arabia 2012. MERS-CoV has the potential to mutate or recombine with other coronaviruses, thus acquiring ability efficiently spread among humans and become pandemic. Its high mortality rate of up 35% absence effective targeted therapies call for development antiviral drugs this pathogen. Since beginning SARS-CoV-2 pandemic, extensive research focused on identifying protease inhibitors treatment SARS-CoV-2. Our intention was therefore assess whether these are viable options combating MERS-CoV. To that end, we used previously established assays quantify inhibition SARS-CoV-2, main proteases. Nirmatrelvir inhibited several proteases, whereas ensitrelvir less broadly active. simulate nirmatrelvir’s clinical use against subsequent resistance development, applied a safe, surrogate virus-based system. Using virus, selected hallmark mutations SARS-CoV-2-M pro , such as T21I, M49L, S144A, E166A/K/V L167F. In current study, pool MERS-CoV-M mutants, characterized modelled steric effect catalytic site mutants S142G, S142R, S147Y A171S.

Language: Английский

Citations

6
Structural review of SARS-CoV-2 antiviral targets DOI Creative Commons
Wen Cui, Yinkai Duan, Gao Yan

et al.

Structure, Journal Year: 2024, Volume and Issue: 32(9), P. 1301 - 1321

Published: Sept. 1, 2024

Language: Английский

Citations

3
Identifying Natural Products as Feline Coronavirus Mpro Inhibitors by Structural-Based Virtual Screening and Enzyme-Based Assays DOI Creative Commons

Zunyun Jiang,

Lianhua Piao,

Changyi Ren

et al.

ACS Omega, Journal Year: 2025, Volume and Issue: 10(2), P. 2092 - 2101

Published: Jan. 10, 2025

The main protease (Mpro) is a pivotal target in the life cycle of feline coronavirus (FCoV), which causes high mortality disease, infectious peritonitis (FIP). Virtual screening was performed against Mpro to find active compounds with low toxicity from library natural products. Eighty-six were selected by using rank docking score and binding pose analysis. In enzyme-based assay, 12 showed more than 40% inhibitory effect on at concentration 200 μmol/L. IC50 values theaflavin 3,3′-digallate (25.0 μmol/L), sennoside C (25.2 pinocembrin-galloyl-HHDP-G (33.3 thonningianin A (50.6 μmol/L) determined. addition, curcuminoids (51.7–64.3% under flavonoids (41.3–60.3% also exhibited certain effects Mpro. Molecular dynamics simulations free energy calculations employed reveal atomic details these results that most formed significant interactions key residues catalytic site, such as His-41, Cys-144, Glu-165. These could serve starting point develop FCoV inhibitors potency.

Language: Английский

Citations

0
Antivirals in COVID‐19: A Focus on Pediatric Cardiac Patients DOI Creative Commons

Darsh Safi,

Farah Khouri,

Rana Zareef

et al.

Canadian Journal of Infectious Diseases and Medical Microbiology, Journal Year: 2025, Volume and Issue: 2025(1)

Published: Jan. 1, 2025

The COVID‐19 pandemic created an unprecedented public health crisis, driven by its rapid global spread and the urgent need for worldwide collaborative interventions to contain it. This urgency spurred search therapeutic agents prevent or manage infection. Among these, various types of antivirals emerged as a prominent treatment option, supported wealth observational studies randomized controlled trials. results from such conflict, with some concluding efficacy others lack thereof, variability also occurring depending on severity in studied population. In addition, many have been explored using trials—the gold standard evaluating intervention—to only limited degree, most evidence behind their use concluded studies. Thus, sheer volume data has made it challenging resolve inconsistencies determine true efficacy. Furthermore, there is paucity literature regarding pediatric population infected COVID‐19, being extrapolated done adult patients. As such, additional trials are needed solidify effectiveness managing particularly underexplored especially vulnerable cardiac Therefore, utilizing trials, this narrative review evaluates rationale antivirals, summarizes findings literature, concludes focused discussion application

Language: Английский

Citations

0