# SELF-MASKED ALDEHYDES AS INHIBITORS OF THE CYSTEINE PROTEASES 3CL PROTEASE, CATHEPSIN L, AND CRUZAIN > **NIH NIH R21** · TEXAS A&M AGRILIFE RESEARCH · 2022 · $233,247 ## Abstract PROJECT SUMMARY Cysteine proteases play essential roles in the causative agents of numerous infectious diseases, including malaria, Chagas disease (CD, caused by the parasite Trypanosoma cruzi), and COVID- 19 (caused by the coronavirus SARS-CoV-2). There are neither vaccines nor well-tolerated therapies available for CD, which results in 50,000 annual deaths in Central and South America, with an estimated 300,000 infected individuals in the US. Cruzain is a cysteine protease that is essential to the establishment and maintenance of human infection by T. cruzi. By February 2021, the COVID-19 pandemic has resulted in 103 million cases worldwide and 2.2 million deaths. Despite the recent arrival of effective vaccines, the emergence of new variants of SARS-CoV-2 may render them less effective over time. Accordingly, the discovery of new therapeutic agents to treat COVID-19 remains a critical, unmet medical need. We recently showed that K11777, an irreversible, covalent inactivator of both cruzain and cathepsin L, potently blocked SARS-CoV-2 infection of mammalian cells by inactivation of the cysteine protease cathepsin L. Consequently, since then K11777 has advanced to Phase 2 clinical trials for the treatment of COVID-19. A recent publication reported that cathepsin L was significantly upregulated in lung autopsy samples from COVID-19 patients, suggesting that this CP not only has a key role in CoV-2 cell entry but also in the severity of human disease. Infection by SARS-CoV-2 requires the action of coronaviral protease 3CL protease (3CL-PR); also a cysteine protease, and consequently is an important drug target for COVID-19. Our approach is to identify inhibitors of cysteine proteases which form reversible covalent bonds with the invariant active-site cysteines of these enzymes. Ideally, selection of an appropriate peptide scaffold for such an inhibitor would provide a compound that potently inhibits more than one CP. Aldehydes are exceptionally potent, covalent, but reversible, inhibitors of cysteine proteases, despite the risk associated with their reactivity and metabolic instability. Here, we seek to re-address aldehydes as potent, reversible enzyme inhibitors by modifying them as intramolecular lactols, or “self-masked” aldehydes (SMAIs). The objective of this proposal is to design, synthesize, and evaluate new SMAIs, including prodrug forms, as novel inhibitors of these three CP drug targets, and evaluate their anti-infective properties in cellular models of CD and COVID-19. We will improve the drug-like properties of these new inhibitors in terms of pharmacokinetics, metabolic stability, and identify additional series of SMAIs. We will utilize prodrug forms of these inhibitors that provide enhanced metabolic stability from which active inhibitors should be released intercellularly upon enzymatic modification. ## Key facts - **NIH application ID:** 10355007 - **Project number:** 1R21AI166624-01 - **Recipient organization:** TEXAS A&M AGRILIFE RESEARCH - **Principal Investigator:** Thomas D Meek - **Activity code:** R21 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2022 - **Award amount:** $233,247 - **Award type:** 1 - **Project period:** 2021-11-04 → 2023-10-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10355007 ## Citation > US National Institutes of Health, RePORTER application 10355007, SELF-MASKED ALDEHYDES AS INHIBITORS OF THE CYSTEINE PROTEASES 3CL PROTEASE, CATHEPSIN L, AND CRUZAIN (1R21AI166624-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10355007. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*