Chemistry:Olgotrelvir

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Olgotrelvir (STI-1558) is an experimental antiviral medication being studied as a potential treatment for COVID-19. It is believed to work by inhibiting the SARS-CoV-2 main protease (Mpro), a key enzyme that SARS-CoV-2 needs to replicate,[1][2][3][4][5] and by blocking viral entry.[2][5][6]

China's National Medical Products Administration (NMPA) granted conditional approval for olgotrelvir for the treatment of adult patients with mild-to-moderate COVID-19 in late 2025.[7][8][9]

Mechanism of action

Olgotrelvir is a prodrug that first converts to its active form, AC1115.[2][6] AC1115 is believed to work by inhibiting the SARS-CoV-2 main protease (also known as 3C-like protease). This protein is a crucial enzyme responsible for cleaving viral polyproteins into functional subunits essential for viral replication. By binding to the active site of the protease, the drug prevents this cleavage process, effectively halting viral assembly and impeding the virus's ability to produce future virions.[1][2][3][6][5]

AC1115 also appears to inhibit cathepsin L (CTSL),[2][6][5] a protein implicated in facilitating viral entry of SARS-CoV-2 into the host cell.[2][6][10][5]

Clinical trials

In September 2023, the drug's developer, Sorrento Therapeutics, announced top-line data that olgotrelvir had met its primary endpoints in a phase III clinical trial that enrolled 1,212 patients with mild or moderate COVID-19. The drug appeared to shorten the recovery time of 11 COVID-19 symptoms in olgotrelvir-treated patients by 2.4 days on average compared to patients in the placebo group. The drug was also shown to reduce the viral load at day 4 in treated patients compared to the placebo group. Side effects were mostly mild and infrequent, with the most common being nausea (1.5% vs. 0.2%) and skin rash (3.3% vs. 0.3%), which occurred more often in the olgotrelvir group.[11][12][13]

References

  1. ↑ 1.0 1.1 "Evaluation of in vitro antiviral activity of SARS-CoV-2 Mpro inhibitor pomotrelvir and cross-resistance to nirmatrelvir resistance substitutions". Antimicrobial Agents and Chemotherapy 67 (11): e0084023. November 2023. doi:10.1128/aac.00840-23. PMID 37800975. "Other examples of Mpro inhibitors in late-stage development include STI-1558, currently in the phase 3 clinical trial in adult subjects with mild or moderate COVID-19 (NCT05716425).". 
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 "Second Generation Oral Mpro Inhibitor for COVID-19 Treatment Proceeds in Phase 3 Study". 26 June 2023. https://www.precisionvaccinations.com/2023/06/26/second-generation-oral-mpro-inhibitor-covid-19-treatment-proceeds-phase-3-study. 
  3. ↑ 3.0 3.1 "Coronavirus disease 2019 (COVID-19) emerging treatments". https://bestpractice.bmj.com/topics/en-us/3000168/emergingtxs. 
  4. ↑ "On the origins of SARS-CoV-2 main protease inhibitors". RSC Medicinal Chemistry 15 (1): 81–118. September 2023. doi:10.1039/D3MD00493G. ISSN 2632-8682. PMID 38283212. 
  5. ↑ 5.0 5.1 5.2 5.3 5.4 "Dual Inhibitors of SARS-CoV-2 3CL Protease and Human Cathepsin L Containing Glutamine Isosteres Are Anti-CoV-2 Agents". Journal of the American Chemical Society 147 (2): 1631–1648. January 2025. doi:10.1021/jacs.4c11620. PMID 39746101. 
  6. ↑ 6.0 6.1 6.2 6.3 6.4 "Olgotrelvir, a dual inhibitor of SARS-CoV-2 Mpro and cathepsin L, as a standalone antiviral oral intervention candidate for COVID-19". Med (New York, N.Y.) 5 (1): 42–61.e23. January 2024. doi:10.1016/j.medj.2023.12.004. PMID 38181791. 
  7. ↑ "Approvals by the China NMPA in 2025". Nature Reviews. Drug Discovery 25 (3): 164–165. March 2026. doi:10.1038/d41573-026-00028-2. PMID 41688808. 
  8. ↑ "Zhejiang Acea Pharma Secures Conditional NMPA Approval for Olgotrelvir Sodium Capsules – First Dual‑Target COVID‑19 Oral Antiviral in China". 5 November 2025. https://flcube.com/?p=45866. 
  9. ↑ "Olgotrelvir Sodium". https://synapse.patsnap.com/drug/a1d187ceceb540cba0d07faf7647dc0e. 
  10. ↑ "Cathepsin L, transmembrane peptidase/serine subfamily member 2/4, and other host proteases in COVID-19 pathogenesis - with impact on gastrointestinal tract". World Journal of Gastroenterology 27 (39): 6590–6600. October 2021. doi:10.3748/wjg.v27.i39.6590. PMID 34754154. 
  11. ↑ "Olgotrelvir as a Single-Agent Treatment of Nonhospitalized Patients with Covid-19". NEJM Evidence 3 (6). June 2024. doi:10.1056/EVIDoa2400026. PMID 38804790. 
  12. ↑ "How To Measure Benefit in a Changing Pandemic - Olgotrelvir for SARS-CoV-2". NEJM Evidence 3 (6). June 2024. doi:10.1056/EVIDe2400144. PMID 38804789. https://evidence.nejm.org/doi/10.1056/EVIDe2400144. 
  13. ↑ "Sorrento Announces Phase 3 Trial Met Primary Endpoint and Key Secondary Endpoint in Mild or Moderate COVID-19 Adult Patients Treated with Ovydso (Olgotrelvir), an Oral Mpro Inhibitor as a Standalone Treatment for COVID-19" (Press release). BioSpace. 12 September 2023. Retrieved 27 December 2023.



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