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Olgotrelvir

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Olgotrelvir
Clinical data
Trade namesOvydso
Other namesSTI-1558, HY-156655, CS-0887294
Routes of
administration		By mouth
Identifiers
  • (2S)-1-hydroxy-2-[[(2S)-2-(1H-indole-2-carbonylamino)-4-methylpentanoyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propane-1-sulfonic acid
CAS Number
PubChem CID
UNII
KEGG
Chemical and physical data
FormulaC22H30N4O7S
Molar mass494.56 g·mol−1
3D model (JSmol)
  • CC(C)CC(C(=O)NC(CC1CCNC1=O)C(O)S(=O)(=O)O)NC(=O)C2=CC3=CC=CC=C3N2
  • InChI=1S/C22H30N4O7S/c1-12(2)9-16(25-21(29)17-10-13-5-3-4-6-15(13)24-17)20(28)26-18(22(30)34(31,32)33)11-14-7-8-23-19(14)27/h3-6,10,12,14,16,18,22,24,30H,7-9,11H2,1-2H3,(H,23,27)(H,25,29)(H,26,28)(H,31,32,33)/t14-,16-,18-,22?/m0/s1
  • Key:IICZZAVAIPTWCL-HBIMBUPRSA-N

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] and by blocking viral entry.[2][5]

Mechanism of action

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Olgotrelvir is a prodrug that first converts to its active form, AC1115.[2][5] 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][5]

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

Clinical trials

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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.[7][8][9]

References

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  1. ^ a b Tong X, Keung W, Arnold LD, Stevens LJ, Pruijssers AJ, Kook S, Lopatin U, Denison M, Kwong AD (November 2023). "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. doi:10.1128/aac.00840-23. PMC 10649086. 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. ^ a b c d e f Hackett DW (26 June 2023). "Second Generation Oral Mpro Inhibitor for COVID-19 Treatment Proceeds in Phase 3 Study". Precision Vaccinations. Retrieved 27 December 2023.
  3. ^ a b "Coronavirus disease 2019 (COVID-19) emerging treatments". BMJ Best Practice US. Archived from the original on 27 December 2023. Retrieved 27 December 2023.
  4. ^ Janin YL (September 2023). "On the origins of SARS-CoV-2 main protease inhibitors". RSC Medicinal Chemistry. 15 (1): 81–118. doi:10.1039/D3MD00493G. ISSN 2632-8682. PMC 10809347. PMID 38283212. S2CID 264103864.
  5. ^ a b c d e Mao L, Shaabani N, Zhang X, Jin C, Xu W, Argent C, Kushnareva Y, Powers C, Stegman K, Liu J, Xie H, Xu C, Bao Y, Xu L, Zhang Y, Yang H, Qian S, Hu Y, Shao J, Zhang C, Li T, Li Y, Liu N, Lin Z, Wang S, Wang C, Shen W, Lin Y, Shu D, Zhu Z, Kotoi O, Kerwin L, Han Q, Chumakova L, Teijaro J, Royal M, Brunswick M, Allen R, Ji H, Lu H, Xu X (January 2024). "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. doi:10.1016/j.medj.2023.12.004. PMID 38181791.
  6. ^ Berdowska I, Matusiewicz M (October 2021). "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. doi:10.3748/wjg.v27.i39.6590. PMC 8554394. PMID 34754154.
  7. ^ Jiang R, Han B, Xu W, Zhang X, Peng C, Dang Q, Sun W, Lin L, Lin Y, Fan L, Lv D, Shao L, Chen Y, Qiu Y, Han L, Kong W, Li G, Wang K, Peng J, Lin B, Tong Z, Lu X, Wang L, Gao F, Feng J, Li Y, Ma X, Wang J, Wang S, Shen W, Wang C, Yan K, Lin Z, Jin C, Mao L, Liu J, Kushnareva Y, Kotoi O, Zhu Z, Royal M, Brunswick M, Ji H, Xu X, Lu H (June 2024). "Olgotrelvir as a Single-Agent Treatment of Nonhospitalized Patients with Covid-19". NEJM Evidence. 3 (6): EVIDoa2400026. doi:10.1056/EVIDoa2400026. PMID 38804790.
  8. ^ Sherman AC, Baden LR (June 2024). "How To Measure Benefit in a Changing Pandemic - Olgotrelvir for SARS-CoV-2". NEJM Evidence. 3 (6): EVIDe2400144. doi:10.1056/EVIDe2400144. PMID 38804789.
  9. ^ "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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