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Browsing by Author "Rivera, Daniel G."
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Item Discovery of potent and selective inhibitors of the Escherichia coli M1-aminopeptidase via multicomponent solid-phase synthesis of tetrazole-peptidomimetics(Elsevier, 2019-01) Méndez, Yanira; De Armas, German; Pérez, Idalia; Rojas, Tamara; Valdés-Tresanco, Mario E.; Izquierdo, Maikel; del Rivero, Maday Alonso; Álvarez-Ginarte, Yoanna María; Valiente, Pedro A.; Soto, Carmen; de León, Lena; Vasco, Aldrin V.; Scott, William L.; Westermann, Bernhard; González-Bacerio, Jorge; Rivera, Daniel G.; Chemistry and Chemical Biology, School of ScienceThe Escherichia coli neutral M1-aminopeptidase (ePepN) is a novel target identified for the development of antimicrobials. Here we describe a solid-phase multicomponent approach which enabled the discovery of potent ePepN inhibitors. The on-resin protocol, developed in the frame of the Distributed Drug Discovery (D3) program, comprises the implementation of parallel Ugi-azide four-component reactions with resin-bound amino acids, thus leading to the rapid preparation of a focused library of tetrazole-peptidomimetics (TPMs) suitable for biological screening. By dose-response studies, three compounds were identified as potent and selective ePepN inhibitors, as little inhibitory effect was exhibited for the porcine ortholog aminopeptidase. The study allowed for the identification of the key structural features required for a high ePepN inhibitory activity. The most potent and selective inhibitor (TPM 11) showed a non-competitive inhibition profile of ePepN. We predicted that both diastereomers of compound TPM 11 bind to a site distinct from that occupied by the substrate. Theoretical models suggested that TPM 11 has an alternative inhibition mechanism that doesn't involve Zn coordination. On the other hand, the activity landscape analysis provided a rationale for our findings. Of note, compound TMP 2 showed in vitro antibacterial activity against Escherichia coli. Furthermore, none of the three identified inhibitors is a potent haemolytic agent, and only two compounds showed moderate cytotoxic activity toward the murine myeloma P3X63Ag cells. These results point to promising compounds for the future development of rationally designed TPMs as antibacterial agents.Item Globally Distributed Drug Discovery of New Antibiotics: Design and Combinatorial Synthesis of Amino Acid Derivatives in the Organic Chemistry Laboratory(ACS, 2019-06) Dounay, Amy B.; O'Donnell, Martin J.; Samaritoni, J. Geno; Popiolek, Lukasz; Schirch, Douglas; Biernasiuk, Anna; Malm, Anna; Lamb, Isaac W.; Mudrack, Kristen; Rivera, Daniel G.; Ojeda, Gerardo M.; Scott, William L.; Chemistry and Chemical Biology, School of ScienceAn experiment for the synthesis of N-acyl derivatives of natural amino acids has been developed as part of the Distributed Drug Discovery (D3) program. Students use solid-phase synthesis techniques to complete a three-step, combinatorial synthesis of six products, which are analyzed using LC–MS and NMR spectroscopy. This protocol is suitable for introductory organic laboratory students and has been successfully implemented at multiple academic sites internationally. Accompanying prelab activities introduce students to SciFinder and to medicinal chemistry design principles. Pairing of these activities with the laboratory work provides students an authentic and cohesive research project experience.Item Multi-Institution Research and Education Collaboration Identifies New Antimicrobial Compounds(American Chemical Society, 2020-12-18) Fuller, Amelia A.; Dounay, Amy B.; Schirch, Douglas; Rivera, Daniel G.; Hansford, Karl A.; Elliott, Alysha G.; Zuegg, Johannes; Cooper, Matthew A.; Blaskovich, Mark A.T.; Hitchens, Jacob R.; Burris-Hiday, Sarah; Tenorio, Kristiana; Mendez, Yanira; Samaritoni, J. Geno; O’Donnell, Martin J.; Scott, William L.; Chemistry and Chemical Biology, School of ScienceNew antibiotics are urgently needed to address increasing rates of multidrug resistant infections. Seventy-six diversely functionalized compounds, comprising five structural scaffolds, were synthesized and tested for their ability to inhibit microbial growth. Twenty-six compounds showed activity in the primary phenotypic screen at the Community for Open Antimicrobial Drug Discovery (CO-ADD). Follow-up testing of active molecules confirmed that two unnatural dipeptides inhibit the growth of Cryptococcus neoformans with a minimum inhibitory concentration (MIC) ≤ 8 μg/mL. Syntheses were carried out by undergraduate students at five schools implementing Distributed Drug Discovery (D3) programs. This report showcases that a collaborative research and educational process is a powerful approach to discover new molecules inhibiting microbial growth. Educational gains for students engaged in this project are highlighted in parallel to the research advances. Aspects of D3 that contribute to its success, including an emphasis on reproducibility of procedures, are discussed to underscore the power of this approach to solve important research problems and to inform other coupled chemical biology research and teaching endeavors.