A5006190441- Trypanosoma species research and implications
- Research on Leishmaniasis Studies
- Computational Drug Discovery Methods
- Synthesis and Biological Evaluation
- Synthesis and biological activity
- Biochemical and Molecular Research
- Microbial Natural Products and Biosynthesis
- Viral gastroenteritis research and epidemiology
- Synthesis and Characterization of Heterocyclic Compounds
- Click Chemistry and Applications
- SARS-CoV-2 and COVID-19 Research
- Bioactive Compounds and Antitumor Agents
- Genomics and Phylogenetic Studies
- Macrophage Migration Inhibitory Factor
- Helminth infection and control
- Virus-based gene therapy research
- Coenzyme Q10 studies and effects
- Pharmacological Effects of Natural Compounds
- Cancer therapeutics and mechanisms
- Cytokine Signaling Pathways and Interactions
- Crystallography and molecular interactions
- Synthesis of Tetrazole Derivatives
- Signaling Pathways in Disease
- Synthesis of β-Lactam Compounds
- Multiple Myeloma Research and Treatments
University of Montana
2021-2025
Center for Discovery
2021-2025
University of California, San Diego
2021-2025
Universidade Federal de Minas Gerais
2016-2024
Universidade Federal de Pernambuco
2013-2019
The main protease (Mpro, 3CLpro) of SARS-CoV-2 is an attractive target in coronaviruses because its crucial involvement viral replication and transcription. Here, we report on the design, synthesis, structure-activity relationships novel small-molecule thioesters as Mpro inhibitors. Compounds 3w 3x exhibited excellent inhibition with kinac/Ki 58,700 M-1 s-1 (Ki = 0.0141 μM) 27,200 0.0332 μM), respectively. In Calu-3 Vero76 cells, compounds 3h, 3i, 3l, 3r, 3v, 3w, displayed antiviral activity...
Abstract Culture-based microbial natural product discovery strategies fail to realize the extraordinary biosynthetic potential detected across earth’s microbiomes. Here we introduce Small Molecule In situ Resin Capture (SMIRC), a culture-independent method obtain products directly from environments in which they are produced. We use SMIRC capture numerous compounds including two new carbon skeletons that were characterized using NMR and contain structural features are, best of our knowledge,...
The worldwide COVID-19 pandemic caused by the coronavirus SARS-CoV-2 urgently demands novel direct antiviral treatments. main protease (Mpro) and papain-like (PLpro) are attractive drug targets among coronaviruses due to their essential role in processing polyproteins translated from viral RNA. In this study, we virtually screened 688 naphthoquinoidal compounds derivatives against Mpro of SARS-CoV-2. Twenty-four were selected evaluated biochemical assays using a fluorogenic substrate....
The main protease (Mpro) of SARS-CoV-2 is a key drug target for the development antiviral therapeutics. Here, we designed and synthesized series small-molecule peptidomimetics with various cysteine-reactive electrophiles. Several compounds were identified as potent Mpro inhibitors, including 8n (IC50 = 0.0752 μM), 8p 0.0887 8r 0.0199 10a 0.0376 10c 0.0177 10f 0.0130 μM). Most them additionally inhibited cathepsin L also active against SARS-CoV-1 MERS-CoV Mpro. In Calu-3 cells, several 8r,...
Human African Trypanosomiasis (HAT) is caused by Trypanosoma brucei. Drug therapy remains challenging due to drug resistance and/or toxicity. New drugs are needed. Using thiosemicarbazones as a starting point, we employed S Se isosteric replacement strategy design 44 analogs which were evaluated against T. brucei in vitro. Compounds divided into eleven groups of four derivatives corresponding thio-, selenosemicarbazones, and their cyclic counterparts, thio- selenazoles. We selected three...
Pseudopeptides are attractive agents for protease inhibition due to their structural similarities the natural substrates of these enzymes, as well enhanced stability and resistance enzymatic degradation. We report three new ketomemicin pseudopeptides (1–3) from extracts marine actinomycete Salinispora pacifica strain CNY-498. Their constitution relative configuration were elucidated using NMR, mass spectrometry, quantum chemical calculations. Using GNPS molecular networking publicly...
The cysteine proteases, cruzain and TbrCATL (rhodesain), are therapeutic targets for Chagas disease Human African Trypanosomiasis, respectively. Among the known inhibitors these we have described N4-benzyl-N2-phenylquinazoline-2,4-diamine (compound 7 in original publication, 1a this study), as a competitive inhibitor (Ki = 1.4 μM). Here, describe synthesis biological evaluation of 22 analogs 1a, containing modifications quinazoline core, substituents positions 2 4 ring. demonstrate low...
Gallinamide A, a metabolite of the marine cyanobacterium Schizothrix sp., selectively inhibits cathepsin L-like cysteine proteases. We evaluated potency gallinamide A and 23 synthetic analogues against intracellular Trypanosoma cruzi amastigotes protease, cruzain. determined co-crystal structures cruzain with two at ∼2 Å. SAR data revealed that N-terminal end is loosely bound weakly contributes in drug–target interactions. At C-terminus, intramolecular π–π stacking interactions between...
Aim: Discovery of novel SARS-CoV-2 main protease (Mpro) inhibitors using a structure-based drug discovery strategy. Materials & methods: Virtual screening employing covalent and noncovalent docking was performed to discover Mpro inhibitors, which were subsequently evaluated in biochemical cellular assays. Results: 91 virtual hits selected for assays, four confirmed as reversible SARS CoV-2 with IC50 values 0.4–3 μM. They also shown inhibit SARS-CoV-1 human cathepsin L. Molecular dynamics...
Schistosomiasis, or bilharzia, is a neglected tropical disease caused by
Computer-Aided Drug Design (CADD) approaches, such as those employing quantitative structure-activity relationship (QSAR) methods, are known for their ability to uncover novel data from large databases. These approaches can help alleviate the lack of biological and chemical data, but some predictions do not generate sufficient positive information be useful screenings. QSAR models often employed explain chemicals design new based on predictions. In this review, we discuss importance set size...
Chagas disease, which is caused by Trypanosoma cruzi, affects more than six million people worldwide. Cruzain the major cysteine protease involved in survival of this parasite. Here, expression, purification and crystallization enzyme are reported. The cruzain crystals diffracted to 1.2 Å resolution, yielding two novel structures: apocruzain bound reversible covalent inhibitor S-methyl thiomethanesulfonate. Mass-spectrometric experiments confirmed presence a methylthiol group attached...
Noroviruses are highly contagious and one of the leading causes acute gastroenteritis worldwide. Due to a lack effective antiviral therapies, there is need diagnose surveil norovirus infections implement quarantine protocols prevent large outbreaks. Currently, gold standard diagnosis uses reverse transcription polymerase chain reaction (RT-PCR), but PCR can have limited availability. Here, we propose combination tunable peptide substrate nanoparticles (AuNPs) colorimetrically detect...
Safe and effective treatments for Chagas disease, a potentially fatal parasitic infection associated with cardiac gastrointestinal pathology caused by the kinetoplastid parasite Trypanosoma cruzi, have yet to be developed. Benznidazole nifurtimox, which are currently only available drugs against T. severe adverse effects questionable efficacy in late stage of disease. Natural products proven rich source new chemotypes other infectious agents. We utilized microscopy-based high-throughput...
Tick-transmitted
Trypanosoma cruzi (Chagas diseases – also named American trypanosomiasis) and T. brucei (human African trypanosomiasis HAT) negatively impact public health, being endemic in several countries leading to thousands of deaths per year.