Inhibitors of SARS-CoV-2 Main Protease (Mpro) as Anti-Coronavirus Agents
Abstract
:1. Introduction
2. The Structure of Mpro
2.1. Substrate Recognition
2.2. The Catalytic Mechanism for the Cleavage of Polyproteins by Mpro
3. Classification of Mpro Inhibitors
3.1. Classification of Mpro Inhibitors by Binding Kinetics
3.1.1. Non-Covalent Inhibitors of Mpro
3.1.2. Covalent Inhibitors of Mpro
3.2. Classification of Mpro Inhibitors by Origin
3.3. Classification of Mpro Inhibitors by the Chemical Structure
3.3.1. Peptidomimetics
3.3.2. Small Molecules
3.4. Classification of Mpro Inhibitors by Electrophilic Warheads
4. Clinical Trials of SARS-CoV-2 Mpro Inhibitors
4.1. Covalent Inhibitors
4.2. Non-Covalent Inhibitors
4.3. Dual Inhibitor of SARS-CoV-2 Mpro and Cathepsin L
5. Conclusions, Challenges, and Future Directions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Peptidomimetics | Small Molecules |
---|---|
Advantages | |
Mimic the complex interactions of natural peptides with their receptors or other targets. | Can interact with a wide range of biological targets. Versatile tools in drug discovery |
Like natural peptides, showed high specificity and selectivity for targets, fewer off-target effects, and reduced toxicity. | Better membrane permeability, easily cross the cell membranes, reaching intracellular targets. |
Improved metabolic stability compared to natural peptides | Good oral bioavailability, more convenient for patients. |
Disadvantages | |
Many peptidomimetics still suffer from poor oral bioavailability and may require parenteral administration. | Small molecules can be rapidly metabolized and excreted, sometimes requiring frequent dosing or leading to short half-lives. |
Compared to small molecules, inadequate membrane permeability | High potential for off-target effects and toxicity. |
Complex and expensive synthetic processes are barriers to large-scale production. | Limited capability to mimic complex and specific interactions of larger biomolecules like peptides. |
They can sometimes elicit immune responses. | More prone to the development of drug resistance. |
Warhead | Mechanism of Action | Example |
---|---|---|
Carbonyl | The nucleophilic addition of the cysteine -SH leads to the formation of a reversible hemithioacetal adduct. | (a) aldehyde GC373 GC376 [86] NK01-63 (coronastat) (b) ketone PF-00835231 PF-07304814 [87] |
α-Ketonamide | The α-ketoamide moiety forms additional non-covalent H bonds with the amino acids of the active site via the carbonyl oxygen and the -OH of the hemithioacetal | Boceprevir [76] Telaprevir [88] UAWJ246 UAWJ248 [20] |
Michael acceptor group | Michael acceptor groups inhibit the enzymes via conjugate addition of the nucleophilic cysteinyl -SH to the electrophilic Cβ of the unsaturated system, producing a nearly irreversible and longer-lasting adduct. | Compound N3 [89,90] SIMR-2418 [34] Cinanserin [32] ML188 [91] |
Nitrile | Due to the difference in electronegativity with the nitrogen atom, the nitrile carbon is vulnerable to nucleophilic addition by the protease’s catalytic cysteine, leading to the formation of a reversible thioimidate covalent adduct. | PF-07321332 (nirmatrelvir) [37] PF-07817883 [92] GST-HG171 (atilotrevir) [36] |
Active Compound (Sponsor) | ClinicalTrials.gov Identifier | Phase | Summary of the Study |
---|---|---|---|
Nilmatrelvir (PF-07321332)/ Ritonavir (Pfizer, New York, NY, USA) | NCT04756531 | 1 | Study of PF-07321332 in healthy participants. |
NCT04960202 | 2/3 | EPIC-HR: Study of Oral PF-07321332/Ritonavir Compared with Placebo in Nonhospitalized High Risk Adults With COVID-19. | |
NCT05047601 | 2/3 | A Study of a Potential Oral Treatment to Prevent COVID-19 in Adults Who Are Exposed to Household Member(s) With a Confirmed Symptomatic COVID-19 Infection. | |
NCT05129475 | 1 | Food Effect Study to Evaluate the Effect of High-Fat Meal on the Relative Bioavailability of PF-07321332 Boosted with Ritonavir in Healthy Adult Participants. | |
NCT05263895 | 1 | Relative Bioavailability Study of 4 Different Formulations of PF-07321332 Relative to the Commercial Tablet Formulation. | |
NCT05339334 | 1 | A Study to Learn About the Study Medicine PF-07321332 and Ritonavir in Adult Healthy Chinese Participants. | |
NCT05441215 | 1 | A Study to Learn About the Medicine (PF-07321332 or Nirmatrelvir/Ritonavir) in Healthy Lactating Women. | |
NCT05263921 | 1 | Relative Bioavailability Study of PF-07321332/Ritonavir Oral Powder Relative to the Commercial Tablets in Healthy Participants. | |
Lufotrelvir (PF-07304814)/ Ritonavir (Pfizer, New York, NY, USA) | NCT04535167 | 1 | First-In-Human Study to Evaluate Safety, Tolerability, And Pharmacokinetics Following Single Ascending and Multiple Ascending Doses of PF-07304814 In Hospitalized Participants With COVID-19. |
NCT04627532 | 1 | Single Ascending Dose Study of Intravenous Infusion of PF 07304814 in Healthy Adult Participants. | |
NCT05050682 | 1 | Study to Investigate the Mass Balance, Metabolism, and Excretion of [14C]-PF-07304814 in Healthy Participants. | |
Ibuzatrelvir (PF- 07817883)/ Ritonavir (Pfizer, New York, NY, USA) | NCT05580003 | 1 | A Study to Learn Safety and Blood Levels of PF-07817883 in Healthy People. |
NCT05799495 | 2 | A Study to Understand the Effect and Safety of the Study Medicine PF-07817883 in Adults Who Have Symptoms of COVID-19 But Are Not Hospitalized. | |
NCT06122194 | 1 | A Study to Learn PF-07817883 Blood Levels After Administration of Tablets of Study Drug to Healthy Adult Volunteers. | |
Atilotrelvir (GST-HG171)/ Ritonavir (Fujian Akeylink Biotechnology Co., Ltd., Ningde, Fujian, China) | NCT05668897 | 1 | Safety, Tolerability and Pharmacokinetic Characteristics Evaluation on GST-HG171 Tablets. |
NCT05656443 | 2/3 | Study of GST-HG171/Ritonavir Compared with Placebo in Patients with Mild to Moderate COVID-19. | |
NCT06106113 | 1 | Pharmacokinetics and Safety of GST-HG171 Tablets in Subjects with Impaired and Normal Liver Function. | |
NCT06084507 | 1 | Food Effects of GST-HG171 Tablets Combined with Ritonavir in Healthy Chinese Participants. | |
NCT06087055 | 1 | Drug-Drug Interaction Study of Itraconazole With GST-HG171/Ritonavir in Healthy Participants. | |
Simnotrelvir (SIM-0417, SSD8432)/ Ritonavir (Jiangsu Simcere Pharmaceutical Co., Ltd., Nanjing, China) | NCT05339646 | 1 | A Phase 1 Clinical Study of SSD8432 in Healthy Adult Subjects. |
NCT05369676 | 1/2 | To Evaluate SSD8432/Ritonavir in Adults With COVID-19. | |
NCT05475834 | 1 | Study to Investigate the Mass Balance and Biotransformation of SIM0417 in Healthy Adult Chinese Male Participants. | |
NCT05506176 | 2/3 | A Clinical Study to Evaluate the Efficacy and Safety of SIM0417 Orally Co-Administered with Ritonavir in Symptomatic Adult Participants with Mild to Moderate COVID-19. | |
NCT05665647 | 1 | Drug-Drug Interaction Study of Itraconazole, Rifampicin and Midazolam with SIM0417/Ritonavir in Healthy Participants. | |
Leritrelwir (RAY1216) (Guangdong Raynovent Biotech Co., Ltd., Guangzhou, China) | NCT05829551 | 1 | The Safety, Tolerability and Pharmacokinetics Study of RAY1216 in Healthy Adult Participants. |
NCT05620160 | 3 | Study of RAY1216 Tablets Compared with Placebo in Patients with Mild to Moderate COVID-19. | |
NCT06031454 | 1 | Drug-durg Interaction of Leritrelvir (RAY1216) With Midazolam, Omeprazole, Rosuvastatin, Verapamil, and Rifampin. | |
NCT06169085 | 1 | Pharmacokinetics of Leritrelvir (Ray1216) in Elder Participants. | |
NCT06160622 | 1 | Pharmacokinetics of Leritrelvir (RAY1216) in Participants with Severe Kidney Disease. | |
NCT06161259 | 1 | Pharmacokinetics of Leritrelvir (RAY1216) in Participants with Hepatic Impairment. | |
NCT06362460 | 1 | Mass Balance Study of [14C] RAY1216 in Healthy Adult Male Subjects in China. | |
Pomotrelvir (PBI-0451) (Pardes Biosciences, Inc., Carlsbad, CA, USA) | NCT05011812 | 1 | Study of PBI-0451 in Healthy Subjects. |
NCT05543707 | 2 | PBI-0451 (Pomotrelvir) Phase 2 Study in Nonhospitalized Symptomatic Adults With COVID-19. | |
Ensitrelvir (S-217622) | jRCT2031210202 * | 1 | A Phase 1 study of S-217622. |
(Nagata Tsute, Osaka, Japan) | |||
(Gomez JuanCarlos, Osaka, Japan) | jRCT2031210350 * | 2/3 | A Phase 2/3 study of S-217622. |
(Timothy Henrich, San Francisco, CA, USA) | NCT06161688 | 2 | Ensitrelvir for Viral Persistence and Inflammation in People Experiencing Long COVID (PREVAIL-LC). |
(Shionogi Inc., Osaka, Japan) | NCT05897541 | 3 | Phase 3 Study of S-217622 in Prevention of Symptomatic SARS-CoV-2 Infection (SCORPIO-PEP). |
NCT05305547 | 3 | A Study to Compare S-217622 With Placebo in Non-Hospitalized Participants With COVID-19 (SCORPIO-HR). | |
(University of Minnesota, Minneapolis, MN, USA) | NCT05605093 | 3 | Strategies and Treatments for Respiratory Infections & Viral Emergencies (STRIVE): Shionogi Protease Inhibitor (Ensitrelvir). |
Mprosevir (WPV01, WU-04)/Ritonavir (Westlake Pharmaceuticals (Hangzhou) Co., Ltd., Hangzhou, China) | NCT06205329 | 1 | Study of WPV01 in Healthy Subjects. |
NCT05752175 | 2 | Study of WPV01 Compared with Placebo in Patients with Mild/Moderate COVID-19 Infection | |
NCT06197217 | 3 | Phase 3 Clinical Study Evaluating the Efficacy and Safety of WPV01 in Patients with Mild/Moderate COVID-19. | |
Olgotrelvir (STI-1558) | NCT05364840 | 1 | Study to Assess the Safety, Tolerability and Pharmacokinetics of STI-1558 in Healthy Volunteers. |
(Sorrento Therapeutics, Inc., San Diego, CA, USA) | |||
(Zhejiang ACEA Pharmaceutical Co., Ltd., Hangzhou, China) | NCT05523739 | 1 | Safety and Efficacy Study of STI-1558 in Healthy Adults and SARS-CoV-2-Positive Patients. |
(Zhejiang ACEA Pharmaceutical Co., Ltd., Hangzhou, China) | NCT05716425 | 3 | Study to Assess the Efficacy and Safety of STI-1558 in Adult Subjects with Mild or Moderate. |
(Zhejiang ACEA Pharmaceutical Co., Ltd., Hangzhou, China) | NCT05754411 | 1 | Study on Mass Balance and Biotransformation of STI-1558 in Healthy Chinese Adult Male Subjects. |
(Zhejiang ACEA Pharmaceutical Co., Ltd., Hangzhou, China) | NCT06044233 | 1 | A Bioequivalence Trial of Fasting Single Oral STI-1558 Capsule in Healthy Chinese Subjects. |
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Zagórska, A.; Czopek, A.; Fryc, M.; Jończyk, J. Inhibitors of SARS-CoV-2 Main Protease (Mpro) as Anti-Coronavirus Agents. Biomolecules 2024, 14, 797. https://doi.org/10.3390/biom14070797
Zagórska A, Czopek A, Fryc M, Jończyk J. Inhibitors of SARS-CoV-2 Main Protease (Mpro) as Anti-Coronavirus Agents. Biomolecules. 2024; 14(7):797. https://doi.org/10.3390/biom14070797
Chicago/Turabian StyleZagórska, Agnieszka, Anna Czopek, Monika Fryc, and Jakub Jończyk. 2024. "Inhibitors of SARS-CoV-2 Main Protease (Mpro) as Anti-Coronavirus Agents" Biomolecules 14, no. 7: 797. https://doi.org/10.3390/biom14070797