() causes visceral, cutaneous, and mucosal leishmaniasis in humans and canine leishmaniasis in dogs. Herein, we describe that -alkyl hydroxamate derivatives displayed potent and selective activity against the amastigote stage of while no activity was observed against promastigotes. Compound showed potent activity against . Moreover, the combination of compound supported on gold nanoparticles and meglumine antimoniate was also effective and improved the activity of these compounds compared to that of the individual treatment. Docking studies showed that compound did not reach highly conserved pocket C and established interactions with the semiconserved residues V44, A45, R242, and E243 in pocket A of LiSIR2rp1. The surface space determined by these four amino acids is not conserved in human sirtuins. Compound represents a new class of selective ligands with antileishmanial activity.
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http://dx.doi.org/10.1021/acs.jmedchem.9b02016 | DOI Listing |
Am J Cancer Res
December 2024
Division of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Institute of Public Health, Florida A&M University Tallahassee, FL 32307, The United States.
The tumor immune microenvironment (TIME) plays a critical role in cancer development and response to immunotherapy. Immune checkpoint inhibitors aim to reverse the immunosuppressive effects of the TIME, but their success has been limited. Immunotherapy directed at PD-1/PD-L1 has been widely employed, yielding positive results.
View Article and Find Full Text PDF( ) is the world's most deadly infectious pathogen and new drugs are urgently required to combat the emergence of multi-(MDR) and extensively-(XDR) drug resistant strains. The bacterium specifically upregulates sterol uptake pathways in infected macrophages and the metabolism of host-derived cholesterol is essential for long-term survival Here, we report the development of antitubercular small molecules that inhibit the cholesterol oxidases CYP125 and CYP142, which catalyze the initial step of cholesterol metabolism. An efficient biophysical fragment screen was used to characterize the structure-activity relationships of CYP125 and CYP142, and identify a non-azole small molecule that can bind to the heme cofactor of both enzymes.
View Article and Find Full Text PDFProteins have proven to be useful agents in a variety of fields, from serving as potent therapeutics to enabling complex catalysis for chemical manufacture. However, they remain difficult to design and are instead typically selected for using extensive screens or directed evolution. Recent developments in protein large language models have enabled fast generation of diverse protein sequences in unexplored regions of protein space predicted to fold into varied structures, bind relevant targets, and catalyze novel reactions.
View Article and Find Full Text PDFRSC Adv
January 2025
Innovative Informatica Technologies Hyderabad Telangana India.
Non-Small Cell Lung Cancer (NSCLC) is a formidable global health challenge, responsible for the majority of cancer-related deaths worldwide. The Platelet-Derived Growth Factor Receptor (PDGFR) has emerged as a promising therapeutic target in NSCLC, given its crucial involvement in cell growth, proliferation, angiogenesis, and tumor progression. Among PDGFR inhibitors, avapritinib has garnered attention due to its selective activity against mutant forms of PDGFR, particularly PDGFRA D842V and KIT exon 17 D816V, linked to resistance against conventional tyrosine kinase inhibitors.
View Article and Find Full Text PDFTetrahedron
February 2025
Department of Chemistry and Biochemistry, Baylor University, One Bear Place, No. 97348, Waco, Texas 76798-7348, United States.
Antibody-drug conjugates (ADCs) have advanced as a mainstay among the most promising cancer therapeutics, offering enhanced antigen targeting and encompassing wide diversity in their linker and payload components. Small-molecule inhibitors of tubulin polymerization have found success as payloads in FDA approved ADCs and represent further promise in next-generation, pre-clinical and developmental ADCs. Unique dual-mechanism payloads (previously designed and synthesized in our laboratories) function as both potent antiproliferative agents and promising vascular disrupting agents capable of imparting selective and effective damage to tumor-associated microvessels.
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