eLife assessment: SARS-CoV-2 methyltransferase nsp10-16 in complex with natural and drug-like purine analogs for guiding structure-based drug discovery DOI Open Access
Yang Yang

Published: July 17, 2024

Non-structural protein 10 (nsp10) and non-structural 16 (nsp16) are part of the RNA synthesis complex, which is crucial for replication severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Nsp16 exhibits 2'-O-methyltransferase activity during viral messenger capping active in a heterodimeric complex with enzymatically inactive nsp10. It has been shown that inactivation nsp10-16 interferes severely replication, making it highly promising drug target. As information on ligands binding to (nsp10-16) still scarce, we screened site potential drug-like fragment-like compounds using X-ray crystallography. The set 234 consists derivatives natural substrate S-adenosyl methionine (SAM) adenine derivatives, some have described previously as methyltransferase inhibitors nsp16 binders. A docking study guided selection many these compounds. Here report structures binders SAM two them, toyocamycin sangivamycin, present additional crystal presence second substrate, Cap0-analog/Cap0-RNA. identified hits were tested solution antiviral cell culture. Our data provide important structural various molecules bind can be used novel starting points selective inhibitor designs.

Language: Английский

Discovery of First-in-Class PROTAC Degraders of SARS-CoV-2 Main Protease DOI Creative Commons

Yugendar R. Alugubelli,

Jing Xiao,

Kaustav Khatua

et al.

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(8), P. 6495 - 6507

Published: April 12, 2024

We have witnessed three coronavirus (CoV) outbreaks in the past two decades, including COVID-19 pandemic caused by SARS-CoV-2. Main protease (MPro), a highly conserved among various CoVs, is essential for viral replication and pathogenesis, making it prime target antiviral drug development. Here, we leverage proteolysis targeting chimera (PROTAC) technology to develop new class of small-molecule antivirals that induce degradation SARS-CoV-2 MPro. Among them, MPD2 was demonstrated effectively reduce MPro protein levels 293T cells, relying on time-dependent, CRBN-mediated, proteasome-driven mechanism. Furthermore, exhibited remarkable efficacy diminishing SARS-CoV-2-infected A549-ACE2 cells. also displayed potent activity against strains enhanced potency nirmatrelvir-resistant viruses. Overall, this proof-of-concept study highlights potential targeted as an innovative approach developing could fight drug-resistant variants.

Language: Английский

Citations

20
The Design, Synthesis and Mechanism of Action of Paxlovid, a Protease Inhibitor Drug Combination for the Treatment of COVID-19 DOI Creative Commons
Miklós Bege, Anikó Borbás

Pharmaceutics, Journal Year: 2024, Volume and Issue: 16(2), P. 217 - 217

Published: Feb. 2, 2024

The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has presented an enormous challenge to health care systems and medicine. As a result of global research efforts aimed at preventing effectively treating SARS-CoV-2 infection, vaccines with fundamentally new mechanisms action some small-molecule antiviral drugs targeting key proteins in the viral cycle have been developed. most effective drug approved date for treatment is PaxlovidTM, which combination two protease inhibitors, nirmatrelvir ritonavir. Nirmatrelvir reversible covalent peptidomimetic inhibitor main (Mpro) SARS-CoV-2, enzyme plays crucial role reproduction. In this combination, ritonavir serves as pharmacokinetic enhancer, it irreversibly inhibits cytochrome CYP3A4 responsible rapid metabolism nirmatrelvir, thereby increasing half-life bioavailability nirmatrelvir. tutorial review, we summarize development pharmaceutical chemistry aspects Paxlovid, covering evolution warhead design, synthesis mechanism well its inhibition mechanism. efficacy Paxlovid novel virus mutants also overviewed.

Language: Английский

Citations

14
Exploring the structural and molecular interaction landscape of nirmatrelvir and Mpro complex: The study might assist in designing more potent antivirals targeting SARS-CoV-2 and other viruses DOI Creative Commons
Chiranjib Chakraborty, Manojit Bhattacharya, Abdulrahman Alshammari

et al.

Journal of Infection and Public Health, Journal Year: 2023, Volume and Issue: 16(12), P. 1961 - 1970

Published: Sept. 30, 2023

Several therapeutics have been developed and approved against SARS-CoV-2 occasionally; nirmatrelvir is one of them. The drug target Mpro, therefore, it necessary to comprehend the structural molecular interaction Mpro-nirmatrelvir complex.Integrative bioinformatics, system biology, statistical models were used analyze macromolecular complex.Using two complexes, study illustrated interactive residues, H-bonds, interfaces. It informed six nine H-bond formations for first second complex, respectively. maximum bond length was observed as 3.33 Å. ligand binding pocket's surface area volume noted 303.485 Å2 295.456 Å3 complex 308.397 304.865 complex. proteome dynamics evaluated by analyzing complex's NMA mobility, eigenvalues, deformability, B-factor. Conversely, a model created assess therapeutic status nirmatrelvir.Our reveals landscape will guide researchers in designing more broad-spectrum antiviral molecules mimicking nirmatrelvir, which assist fighting other infectious viruses. also help prepare future epidemics or pandemics.

Language: Английский

Citations

14
Covalent small-molecule inhibitors of SARS-CoV-2 Mpro: Insights into their design, classification, biological activity, and binding interactions DOI
Ahmed M. Shawky, Faisal A. Almalki, Hayat Ali Alzahrani

et al.

European Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 277, P. 116704 - 116704

Published: Aug. 8, 2024

Language: Английский

Citations

5
Determination of SARS-CoV-2 Main Protease (Mpro) Activity Based on Electrooxidation of Tyrosine Residue of a Model Peptide DOI
Tatiana A. Filippova, Rami A. Masamrekh,

Tatiana Farafonova

et al.

Biochemistry (Moscow), Journal Year: 2025, Volume and Issue: 90(1), P. 120 - 131

Published: Jan. 1, 2025

Language: Английский

Citations

0
Identification of lead small molecules for the design and development of potent severe acute respiratory syndrome coronavirus 2 main protease inhibitors DOI Creative Commons
Elvis Awuni

Journal of Chemical Research, Journal Year: 2025, Volume and Issue: 49(2)

Published: March 1, 2025

The repercussions of the COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are catastrophic, and world has yet to achieve full recovery. Several inhibitors targeting SARS-CoV-2 main protease experiencing diminished efficacy owing resistance-inducing mutations. current situation implies that quest find potent resilient drugs overcome resistance must be a continuous effort. Here, multiple receptor virtual screening molecular dynamics (MD) simulation techniques were employed identify novel binders from an integrated small-molecule database as leads for discovery, design, development antivirals immune protease. was initially screened separately against five structures with different substrate-binding site conformations using GOLD program, after which fitness score control compound used cutoff create shortlist potential hits in each case. Then, 21 compounds at intersection all shortlists selected hits. subjected MD simulations, identifying four capable remaining bound up 100 ns. Analysis mode binding interactions between revealed fit better into conserved subpockets than interact important amino acid residues. Conjointly, energy, toxicity analysis results further demonstrated promising augment fight resistance.

Language: Английский

Citations

0
Generative artificial intelligence performs rudimentary structural biology modeling DOI Creative Commons
Alexander M. Ille, Christopher Markosian, S.K. Burley

et al.

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

Published: Aug. 21, 2024

Natural language-based generative artificial intelligence (AI) has become increasingly prevalent in scientific research. Intriguingly, capabilities of pre-trained transformer (GPT) language models beyond the scope natural tasks have recently been identified. Here we explored how GPT-4 might be able to perform rudimentary structural biology modeling. We prompted model 3D structures for 20 standard amino acids and an α-helical polypeptide chain, with latter incorporating Wolfram mathematical computation. also used interaction analysis between anti-viral nirmatrelvir its target, SARS-CoV-2 main protease. Geometric parameters generated typically approximated close experimental references. However, modeling was sporadically error-prone molecular complexity not well tolerated. Interaction further revealed ability identify specific acid residues involved ligand binding along corresponding bond distances. Despite current limitations, show capacity AI basic atomic-scale accuracy.

Language: Английский

Citations

2
SARS-CoV-2 methyltransferase nsp10-16 in complex with natural and drug-like purine analogs for guiding structure-based drug discovery DOI Creative Commons
Viviane Kremling, Sven Falke, Yaiza Fernández-García

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: March 13, 2024

Abstract Non-structural protein 10 (nsp10) and non-structural 16 (nsp16) are part of the RNA synthesis complex, which is crucial for replication severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Nsp16 exhibits 2’- O -methyltransferase activity during viral messenger capping active in a heterodimeric complex with enzymatically inactive nsp10. It has been shown that inactivation nsp10-16 interferes severely replication, making it highly promising drug target. As information on ligands binding to (nsp10-16) still scarce, we screened site potential drug-like fragment-like compounds using X-ray crystallography. The set 234 consists derivatives natural substrate S -adenosyl methionine (SAM) adenine derivatives, some have described previously as methyltransferase inhibitors nsp16 binders. A docking study guided selection many these compounds. Here report structures binders SAM two them, toyocamycin sangivamycin, present additional crystal presence second substrate, Cap0-analog/Cap0-RNA. identified hits were tested solution antiviral cell culture. Our data provide important structural various molecules bind can be used novel starting points selective inhibitor designs.

Language: Английский

Citations

2
The Key Site Variation and Immune Challenges in SARS-CoV-2 Evolution DOI Creative Commons
Ying Liu,

Qing Ye

Vaccines, Journal Year: 2023, Volume and Issue: 11(9), P. 1472 - 1472

Published: Sept. 10, 2023

Coronavirus disease 2019 (COVID-19) is a worldwide public health and economic threat, virus variation amplifies the difficulty in epidemic prevention control. The structure of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been studied extensively now well defined. S protein most distinguishing feature terms infection immunity, mediating entrance inducing neutralizing antibodies. its essential components are also promising target to develop vaccines antibody-based drugs. Therefore, key site mutation gene high interest. Among them, RBD, NTD, furin cleavage sites mutable regions with serious consequences for SARS-CoV-2 biological characteristics, including infectivity, pathogenicity, natural vaccine efficacy, antibody therapeutics. We aware that this outbreak may not be last. narrative review, we summarized viral prevalence condition, discussed specific amino acid replacement associated immune challenges attempted sum up some control strategies by reviewing literature on previously published research about assist clarifying pathway developing countermeasures against such viruses as soon possible.

Language: Английский

Citations

5
Discovery of First-in-Class PROTAC Degraders of SARS-CoV-2 Main Protease DOI Open Access

Yugendar R. Alugubelli,

Jing Xiao,

Kaustav Khatua

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Sept. 29, 2023

We have witnessed three coronavirus (CoV) outbreaks in the past two decades, including COVID-19 pandemic caused by SARS-CoV-2. Main protease (M

Language: Английский

Citations

5