ArticleAntimicrobial agents and chemotherapy2014
Reversible cysteine protease inhibitors show promise for a Chagas disease cure.
Article in Antimicrobial agents and chemotherapy, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers, 1 of them a synthesis that pooled it.
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Who cites it
39 citing papers in PubMed, 1 synthesis or guideline pooled it, 103 citations in OpenAlex.
- Discovery of Novel Inhibitors of Cruzain Cysteine Protease ofCurrent medicinal chemistry · 2024Pooled it
- Revisiting cysteine protease function inMicrobiology spectrum · 2026Article
- Machine Learning-Guided Repositioning of a SARS-CoV-2-Targeting Molecular Series as Cruzain Inhibitors.ChemMedChem · 2026Article
- Thiosulfonate-Based Targeted Covalent Cruzipain Inhibitors with Enhanced Bioactivity Translation for Antichagasic Therapy.ACS medicinal chemistry letters · 2025Article
- Discovery of a Potent Triazole-Based Reversible Targeted Covalent Inhibitor of Cruzipain.ACS medicinal chemistry letters · 2025Article
- Structure-Aided Computational Design of Triazole-Based Targeted Covalent Inhibitors of Cruzipain.Molecules (Basel, Switzerland) · 2024Article
- Oral Pyronaridine Tetraphosphate Reduces Tissue Presence of Parasites in a Mouse Model of Chagas Disease.ACS omega · 2024Article
- On the origins of SARS-CoV-2 main protease inhibitors.RSC medicinal chemistry · 2024Review
- Drug Discovery Efforts to Identify Novel Treatments for Neglected Tropical Diseases - Cysteine Protease Inhibitors.Current medicinal chemistry · 2024Review
- Targeting SmCB1: Perspectives and Insights to Design Antischistosomal Drugs.Current medicinal chemistry · 2024Review
- Covalent Inhibitors for Neglected Diseases: An Exploration of Novel Therapeutic Options.Pharmaceuticals (Basel, Switzerland) · 2023Review
- Preclinical Studies and Drug Combination of Low-Cost Molecules for Chagas Disease.Pharmaceuticals (Basel, Switzerland) · 2022Article
- The history, mechanism, and perspectives of nirmatrelvir (PF-07321332): an orally bioavailable main protease inhibitor used in combination with ritonavir to reduce COVID-19-related hospitalizations.Medicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agents · 2022Review
- Structural Optimization and Biological Activity of Pyrazole Derivatives: Virtual Computational Analysis, Recovery Assay and 3D Culture Model as Potential Predictive Tools of Effectiveness againstMolecules (Basel, Switzerland) · 2021Article
- Benznidazole Treatment: Time- and Dose-Dependence Varies with thePathogens (Basel, Switzerland) · 2021Article
- Strecker-Derived Methodology for Library Synthesis ofACS omega · 2021Article
- An Overview on the Therapeutics of Neglected Infectious Diseases-Leishmaniasis and Chagas Diseases.Frontiers in chemistry · 2021Review
- Review on Experimental Treatment Strategies AgainstJournal of experimental pharmacology · 2021Review
- Repurposing Carvedilol as a Novel Inhibitor of theFrontiers in cellular and infection microbiology · 2021Article
- Multiparameter Optimization of Trypanocidal Cruzain Inhibitors WithFrontiers in pharmacology · 2021Article
Corrections and comments
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Authors and funding
10 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The cysteine protease cruzipain is essential for the viability, infectivity, and virulence of Trypanosoma cruzi, the causative agent of Chagas disease. Thus, inhibitors of cruzipain are considered promising anti-T. cruzi chemotherapeutic agents. Reversible cruzipain inhibitors containing a nitrile "warhead" were prepared and demonstrated 50% inhibitory concentrations (IC50s) as potent as 1 nM in baculovirus-generated cruzipain enzyme assays. In epimastigote and intracellular amastigote in vitro assays, the most potent compounds demonstrated antiparasitic behavior in the 5 to 10 μM IC50 range; however, trypomastigote production from the amastigote form was ∼90 to 95% inhibited at 2 μM. Two key compounds, Cz007 and Cz008, with IC50s of 1.1 and 1.8 nM, respectively, against the recombinant enzyme were tested in a murine model of acute T. cruzi infection, with oral dosing in chow for 28 days at doses from 3 to 50 mg/kg of body weight. At 3 mg/kg of Cz007 and 3 mg/kg of Cz008, the blood parasitemia areas under the concentration-time curves were 16% and 25% of the untreated group, respectively. At sacrifice, 24 days after immunosuppression with cyclophosphamide, parasite presence in blood, heart, and esophagus was evaluated. Based on negative quantitative PCR results in all three tissues, cure rates in surviving animals were 90% for Cz007 at 3 mg/kg, 78% for Cz008 at 3 mg/kg, and 71% for benznidazole, the control compound, at 50 mg/kg.
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