Olgotrelvir Explained

Tradename:

Ovydso

Routes Of Administration:

By mouth

Cas Number:

2763596-71-8

Pubchem:

166157331

Unii:

ZP3BDH359D

Kegg:

D12777

Synonyms:

STI-1558, HY-156655, CS-0887294

Iupac Name:

(2S)-1-hydroxy-2-(2S)-2-(1H-indole-2-carbonylamino)-4-methylpentanoylamino]-3-[(3S)-2-oxopyrrolidin-3-yl]propane-1-sulfonic acid| C = 22 | H =30 | N = 4 | O = 7 | S = 1| SMILES = CC(C)CC(C(=O)NC(CC1CCNC1=O)C(O)S(=O)(=O)O)NC(=O)C2=CC3=CC=CC=C3N2| StdInChI = 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| StdInChI_comment = | StdInChIKey = IICZZAVAIPTWCL-HBIMBUPRSA-N| density = | density_notes = | melting_point = | melting_high = | melting_notes = | boiling_point = | boiling_notes = | solubility = | sol_units = | specific_rotation = }}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 (M^pro), a key enzyme that SARS-CoV-2 needs to replicate,^{[1] [2] [3] [4]} and by blocking viral entry.^[5]

Mechanism of action

Olgotrelvir is a prodrug that first converts to its active form, AC1115. 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.

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

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.^{[7] [8]}

References

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Notes and References

1. Tong X, Keung W, Arnold LD, Stevens LJ, Pruijssers AJ, Kook S, Lopatin U, Denison M, Kwong AD . 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 . 37800975 . 10649086 . 10.1128/aac.00840-23 . 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. Web site: Hackett . Don Ward . Second Generation Oral Mpro Inhibitor for COVID-19 Treatment Proceeds in Phase 3 Study . Precision Vaccinations . 26 June 2023 . 27 December 2023.
3. Web site: Coronavirus disease 2019 (COVID-19) emerging treatments . BMJ Best Practice US . 27 December 2023 . https://web.archive.org/web/20231227064401/https://bestpractice.bmj.com/topics/en-us/3000168/emergingtxs . 27 December 2023.
4. Janin YL . On the origins of SARS-CoV-2 main protease inhibitors . RSC Medicinal Chemistry . September 2023 . 15 . 1 . 81–118 . 2632-8682 . 10.1039/D3MD00493G. 38283212 . 10809347 . October 13, 2024 . 264103864 .
5. 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 . 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 . 38181791 . 10.1016/j.medj.2023.12.004 . free .
6. Berdowska I, Matusiewicz M . 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 . 34754154 . 8554394 . 10.3748/wjg.v27.i39.6590. free .
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 . Olgotrelvir as a Single-Agent Treatment of Nonhospitalized Patients with Covid-19 . NEJM Evidence . 3 . 6 . June 2024 . 38804790 . 10.1056/EVIDoa2400026.
8. . 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 . BioSpace . 12 September 2023 . 27 December 2023.