SARS-CoV-2 Mpro Inhibitors: Achieved Diversity, Developing Resistance and Future Strategies DOI Creative Commons
Conrad Fischer,

Jenson R. Feys

Future Pharmacology, Journal Year: 2023, Volume and Issue: 3(1), P. 80 - 107

Published: Jan. 9, 2023

While the COVID-19 pandemic seems to be on its decline, unclear impacts of long-COVID cases, breakthrough infections in immunocompromised individuals, vaccine hesitancy, and inhomogeneous health-care accessibility constitute a not underestimated threat. These along with preparedness, ask for an alert identification new drugs optimization existing as therapeutic treatment options this potential future diseases. Mpro inhibitors were identified early potent drug candidates against coronaviruses, since they target viable processing machinery within virus, i.e., main protease that cleaves polyproteins encoded by viral RNA into functional proteins. Different strategies, including reversible irreversible inhibition well allosteric inhibitors, mostly from repurposing endeavors, have been explored design SARS-CoV-2 antivirals. Ambitious screening efforts uttered outstanding chemical structural diversity, which has led half dozen lead compounds being currently clinical trials emergency FDA approval ritonavir-boosted nirmatrelvir therapeutic. This comprehensive analysis achieved inhibitor diversity sorted irreversible, reversible, binders, discussion emerging resistance reports possible evasion is aimed at stimulating continuing efforts.

Language: Английский

Therapeutic strategies for COVID-19: progress and lessons learned DOI Open Access
Guangdi Li, Rolf Hilgenfeld, Richard J. Whitley

et al.

Nature Reviews Drug Discovery, Journal Year: 2023, Volume and Issue: 22(6), P. 449 - 475

Published: April 19, 2023

Language: Английский

Citations

420
Incorporating Selenium into Heterocycles and Natural Products─From Chemical Properties to Pharmacological Activities DOI
Wei Hou, Hongtao Xu

Journal of Medicinal Chemistry, Journal Year: 2022, Volume and Issue: 65(6), P. 4436 - 4456

Published: March 4, 2022

Selenium (Se)-containing compounds have emerged as potential therapeutic agents for the treatment of a range diseases. Through tremendous effort, considerable knowledge has been acquired to understand complex chemical properties and biological activities selenium, especially after its incorporation into bioactive molecules. From this perspective, we compiled extensive literature evidence summarize critically discuss relationship between pharmacological selenium strategic organic molecules, heterocycles natural products. We also provide perspectives regarding challenges in selenium-based medicinal chemistry future research directions.

Language: Английский

Citations

184
The SARS‐CoV‐2 main protease (Mpro): Structure, function, and emerging therapies for COVID‐19 DOI
Qing Hu, Yuan Xiong, Guanghao Zhu

et al.

MedComm, Journal Year: 2022, Volume and Issue: 3(3)

Published: July 14, 2022

The main proteases (M

Language: Английский

Citations

148
Structural basis for replicase polyprotein cleavage and substrate specificity of main protease from SARS-CoV-2 DOI Creative Commons
Yao Zhao, Yan Zhu, Xiang Liu

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2022, Volume and Issue: 119(16)

Published: April 5, 2022

The main protease (Mpro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a key enzyme, which extensively digests CoV replicase polyproteins essential for viral replication and transcription, making it an attractive target antiviral drug development. However, the molecular mechanism how Mpro SARS-CoV-2 polyproteins, releasing nonstructural proteins (nsps), its substrate specificity remain largely unknown. Here, we determine high-resolution structures in resting state, precleavage postcleavage constituting full cycle cleavage. show delicate conformational changes that occur during polyprotein processing. Further, solve mutant (H41A) complex with six native cleavage substrates from demonstrate can recognize sequences as long 10 residues but only have special selectivity four subsites. These structural data provide basis to develop potent new inhibitors against SARS-CoV-2.

Language: Английский

Citations

130
Progress and Challenges in Targeting the SARS-CoV-2 Papain-like Protease DOI
Haozhou Tan, Yanmei Hu, Prakash D. Jadhav

et al.

Journal of Medicinal Chemistry, Journal Year: 2022, Volume and Issue: 65(11), P. 7561 - 7580

Published: May 27, 2022

SARS-CoV-2 is the causative agent of COVID-19 pandemic. The approval vaccines and small-molecule antivirals vital in combating viral polymerase inhibitors remdesivir molnupiravir main protease inhibitor nirmatrelvir/ritonavir have been approved by U.S. FDA. However, emergence variants concern/interest calls for additional with novel mechanisms action. papain-like (PLpro) mediates cleavage polyprotein modulates host's innate immune response upon infection, rendering it a promising antiviral drug target. This Perspective highlights major achievements structure-based design high-throughput screening PLpro since beginning Encouraging progress includes non-covalent favorable pharmacokinetic properties first-in-class covalent inhibitors. In addition, we offer our opinion on knowledge gaps that need to be filled advance clinic.

Language: Английский

Citations

119
Targeting SARS-CoV-2 Main Protease for Treatment of COVID-19: Covalent Inhibitors Structure–Activity Relationship Insights and Evolution Perspectives DOI Creative Commons
Gabriele La Monica, Alessia Bono, Antonino Lauria

et al.

Journal of Medicinal Chemistry, Journal Year: 2022, Volume and Issue: 65(19), P. 12500 - 12534

Published: Sept. 28, 2022

The viral main protease is one of the most attractive targets among all key enzymes involved in SARS-CoV-2 life cycle. Covalent inhibition cysteine145 MPRO with selective antiviral drugs will arrest replication process virus without affecting human catalytic pathways. In this Perspective, we analyzed silico, vitro, and vivo data representative examples covalent inhibitors reported literature to date. particular, studied molecules were classified into eight different categories according their reactive electrophilic warheads, highlighting differences between reversible/irreversible mechanism inhibition. Furthermore, analyses recurrent pharmacophoric moieties stereochemistry chiral carbons reported. noncovalent silico protocols, provided would be useful for scientific community discover new more efficient inhibitors.

Language: Английский

Citations

102
Small molecules in the treatment of COVID-19 DOI Creative Commons
Sibei Lei, Xiaohua Chen, Jieping Wu

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: Dec. 5, 2022

Abstract The outbreak of COVID-19 has become a global crisis, and brought severe disruptions to societies economies. Until now, effective therapeutics against are in high demand. Along with our improved understanding the structure, function, pathogenic process SARS-CoV-2, many small molecules potential anti-COVID-19 effects have been developed. So far, several antiviral strategies were explored. Besides directly inhibition viral proteins such as RdRp M pro , interference host enzymes including ACE2 proteases, blocking relevant immunoregulatory pathways represented by JAK/STAT, BTK, NF-κB, NLRP3 pathways, regarded feasible drug development. development treat achieved strategies, computer-aided lead compound design screening, natural product discovery, repurposing, combination therapy. Several representative remdesivir paxlovid proved or authorized emergency use countries. And candidates entered clinical-trial stage. Nevertheless, due epidemiological features variability issues it is necessary continue exploring novel COVID-19. This review discusses current findings for treatment. Moreover, their detailed mechanism action, chemical structures, preclinical clinical efficacies discussed.

Language: Английский

Citations

82
Targeting SARS-CoV-2 Proteases for COVID-19 Antiviral Development DOI Creative Commons
Zongyang Lv,

Kristin E. Cano,

Lijia Jia

et al.

Frontiers in Chemistry, Journal Year: 2022, Volume and Issue: 9

Published: Feb. 3, 2022

The emergence of severe acute respiratory syndrome (SARS-CoV-2) in 2019 marked the third occurrence a highly pathogenic coronavirus human population since 2003. As death toll surpasses 5 million globally and economic losses continue, designing drugs that could curtail infection disease progression is critical. In US, three effective Food Drug Administration (FDA)–authorized vaccines are currently available, Remdesivir approved for treatment hospitalized patients. However, moderate vaccination rates sustained evolution new viral variants necessitate ongoing search antivirals. Several proteins have been prioritized as SARS-CoV-2 antiviral drug targets, among them papain-like protease (PLpro) main (Mpro). Inhibition these proteases would target replication, maturation, suppression host innate immune responses. Knowledge inhibitors assays viruses were quickly adopted research. Potential candidates identified to show inhibitory effects against PLpro Mpro, both biochemical replication cells. These results encourage further optimizations improve prophylactic therapeutic efficacy. this review, we examine latest developments potential small-molecule peptide how structural biology greatly facilitates process.

Language: Английский

Citations

77
Synthesis of New Organoselenium-Based Succinanilic and Maleanilic Derivatives and In Silico Studies as Possible SARS-CoV-2 Main Protease Inhibitors DOI Creative Commons
Saad Shaaban, Yasair S. Al‐Faiyz, Ghayah M. Alsulaim

et al.

Inorganics, Journal Year: 2023, Volume and Issue: 11(8), P. 321 - 321

Published: July 29, 2023

Herein we report the synthesis of organic selenide-based maleanilic and succinanilic acids in good yields (up to 95%). Their structural identities were elucidated by spectroscopic techniques (e.g., IR, 1H- & 13C-NMR, MS). The ADMET analysis, molecule electrostatic potential map, DFT, frontier molecular orbital used study organoselenium compounds’ pharmacokinetics, drug-likeness characteristics, geometries, chemical electronic properties. Moreover, a docking tool was employed investigate selenides’ ability inhibit SARS-CoV-2 Mpro target (PDB: 7BFB). Within this context, selenides exhibited promising binding affinities receptor following order (12 > 11 10 9 7 8). Furthermore, dynamics simulations also carried out for 200 ns evaluate exact behavior most active compound (12) within pocket compared with its co-crystallized inhibitor (Co).

Language: Английский

Citations

53
Structure and function of SARS-CoV and SARS-CoV-2 main proteases and their inhibition: A comprehensive review DOI Creative Commons
Xin Li, Yongcheng Song

European Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 260, P. 115772 - 115772

Published: Aug. 28, 2023

Language: Английский

Citations

52