Self-Masked Aldehyde Inhibitors: A Novel Strategy for Inhibiting Cysteine Proteases.

Autor:	Li L; Department of Biochemistry and Biophysics, Texas A&M University, 300 Olsen Blvd, College Station, Texas 77843, United States., Chenna BC; Department of Biochemistry and Biophysics, Texas A&M University, 300 Olsen Blvd, College Station, Texas 77843, United States., Yang KS; Department of Chemistry, Texas A&M University, 580 Ross Street, College Station, Texas 77843, United States., Cole TR; Department of Biochemistry and Biophysics, Texas A&M University, 300 Olsen Blvd, College Station, Texas 77843, United States., Goodall ZT; Department of Biochemistry and Biophysics, Texas A&M University, 300 Olsen Blvd, College Station, Texas 77843, United States., Giardini M; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, 9500 Gilman Dr, La Jolla, California 92093, United States., Moghadamchargari Z; Department of Chemistry, Texas A&M University, 580 Ross Street, College Station, Texas 77843, United States., Hernandez EA; Department of Biochemistry and Biophysics, Texas A&M University, 300 Olsen Blvd, College Station, Texas 77843, United States., Gomez J; Department of Biochemistry and Biophysics, Texas A&M University, 300 Olsen Blvd, College Station, Texas 77843, United States., Calvet CM; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, 9500 Gilman Dr, La Jolla, California 92093, United States., Bernatchez JA; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, 9500 Gilman Dr, La Jolla, California 92093, United States., Mellott DM; Department of Biochemistry and Biophysics, Texas A&M University, 300 Olsen Blvd, College Station, Texas 77843, United States., Zhu J; Department of Biochemistry and Biophysics, Texas A&M University, 300 Olsen Blvd, College Station, Texas 77843, United States., Rademacher A; Department of Biochemistry and Biophysics, Texas A&M University, 300 Olsen Blvd, College Station, Texas 77843, United States., Thomas D; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, 9500 Gilman Dr, La Jolla, California 92093, United States., Blankenship LR; Department of Chemistry, Texas A&M University, 580 Ross Street, College Station, Texas 77843, United States., Drelich A; Department of Microbiology and Immunology, University of Texas Medical Branch, 301 University Blvd, Galveston, Texas 77555, United States., Laganowsky A; Department of Chemistry, Texas A&M University, 580 Ross Street, College Station, Texas 77843, United States., Tseng CK; Department of Microbiology and Immunology, University of Texas Medical Branch, 301 University Blvd, Galveston, Texas 77555, United States., Liu WR; Department of Biochemistry and Biophysics, Texas A&M University, 300 Olsen Blvd, College Station, Texas 77843, United States.; Department of Chemistry, Texas A&M University, 580 Ross Street, College Station, Texas 77843, United States., Wand AJ; Department of Biochemistry and Biophysics, Texas A&M University, 300 Olsen Blvd, College Station, Texas 77843, United States., Cruz-Reyes J; Department of Biochemistry and Biophysics, Texas A&M University, 300 Olsen Blvd, College Station, Texas 77843, United States., Siqueira-Neto JL; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, 9500 Gilman Dr, La Jolla, California 92093, United States., Meek TD; Department of Biochemistry and Biophysics, Texas A&M University, 300 Olsen Blvd, College Station, Texas 77843, United States.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2021 Aug 12; Vol. 64 (15), pp. 11267-11287. Date of Electronic Publication: 2021 Jul 21.
DOI:	10.1021/acs.jmedchem.1c00628
Abstrakt:	Cysteine proteases comprise an important class of drug targets, especially for infectious diseases such as Chagas disease (cruzain) and COVID-19 (3CL protease, cathepsin L). Peptide aldehydes have proven to be potent inhibitors for all of these proteases. However, the intrinsic, high electrophilicity of the aldehyde group is associated with safety concerns and metabolic instability, limiting the use of aldehyde inhibitors as drugs. We have developed a novel class of self-masked aldehyde inhibitors (SMAIs) for cruzain, the major cysteine protease of the causative agent of Chagas disease- Trypanosoma cruzi . These SMAIs exerted potent, reversible inhibition of cruzain ( K i * = 18-350 nM) while apparently protecting the free aldehyde in cell-based assays. We synthesized prodrugs of the SMAIs that could potentially improve their pharmacokinetic properties. We also elucidated the kinetic and chemical mechanism of SMAIs and applied this strategy to the design of anti-SARS-CoV-2 inhibitors.
Databáze:	MEDLINE
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