Rodolfo Mota
Deparment: Department of Chemistry

Items: 5

Views: 1097

1. Isoleucine-glycine-aspartic acid peptidomimetics as novel wound-healing agents in vitro

Author:Matheson, M;Wright, C;Marquez, R


2. Structure-activity analysis of CJ-15,801 analogues that interact with Plasmodium falciparum pantothenate kinase and inhibit parasite proliferation

Author:Spry, C;Sewell, AL;Hering, Y;Villa, MVJ;Weber, J;Hobson, SJ;Harnor, SJ;Gul, S;Marquez, R;Saliba, KJ


Abstract:Survival of the human malaria parasite Plasmodium falciparum is dependent on pantothenate (vitamin B-5), a precursor of the fundamental enzyme cofactor coenzyme A. CJ-15,801, an enamide analogue of pantothenate isolated from the fungus Seimatosporium sp. CL28611, was previously shown to inhibit P. falciparum proliferation in vitro by targeting pantothenate utilization. To inform the design of next generation analogues, we set out to synthesize and test a series of synthetic enamide-bearing pantothenate analogues. We demonstrate that conservation of the R-pantoyl moiety and the trans-substituted double bond of CJ-15,801 is important for the selective, on-target antiplasmodial effect, while replacement of the carboxyl group is permitted, and, in one case, favored. Additionally, we show that the antiplasmodial potency of CJ-15,801 analogues that retain the R-pantoyl and trans-substituted enamide moieties correlates with inhibition of P. falciparum pantothenate kinase (PfPanK)-catalyzed pantothenate phosphorylation, implicating the interaction with PfPanK as a key determinant of antiplasmodial activity. (C) 2017 Elsevier Masson SAS. All rights reserved.
3. Novel compounds targeting the enterohemorrhagic Escherichia coli type three secretion system reveal insights into mechanisms of secretion inhibition

Author:Zambelloni, R;Connolly, JPR;Uribe, AH;Burgess, K;Marquez, R;Roe, AJ


Abstract:Anti-virulence (AV) compounds are a promising alternative to traditional antibiotics for fighting bacterial infections. The Type Three Secretion System (T3SS) is a well-studied and attractive AV target, given that it is widespread in more than 25 species of Gram-negative bacteria, including enterohemorrhagic E. coli (EHEC), and as it is essential for host colonization by many pathogens. In this work, we designed, synthesized and tested a new series of compounds that block the functionality of the T3SS of EHEC. Affinity chromatography experiments identified the primary target of the compounds as the T3SS needle pore protein EspD, which is essential for effector protein translocation into host cells. These data were supported by mechanistic studies that determined the coiled-coil domain 1 of EspD as a key compound-binding site, thereby preventing correct assembly of the T3SS complex on the cell surface. However, binding of inhibitors to EspD or deletion of EspD itself did not result in transcriptional down-regulation of effector proteins. Instead, we found the compounds to exhibit dual-functionality by also down-regulating transcription of the entire chromosomal locus encoding the T3SS, further demonstrating their desirability and effectiveness.
4. Flexible synthesis of polyfunctionalised 3-fluoropyrroles

Author:Cogswell, TJ;Donald, CS;Marquez, R


Abstract:An efficient and selective approach for the synthesis of polyfunctionalised 3-fluoropyrroles has been developed starting from commercial aldehydes. The methodology is concise, efficient and allows for the modular and systematic assembly of polysubstituted 3-fluoropyrroles. This synthesis provides an alternative and highly convergent strategy for the generation of these chemically and biologically important units.
5. Mutations in the pantothenate kinase of Plasmodium falciparum confer diverse sensitivity profiles to antiplasmodial pantothenate analogues

Author:Tjhin, ET;Spry, C;Sewell, AL;Hoegl, A;Barnard, L;Sexton, AE;Siddiqui, G;Howieson, VM;Maier, AG;Creek, DJ;Strauss, E;Marquez, R;Auclair, K;Saliba, KJ

Source:PLOS PATHOGENS,2018,Vol.14

Abstract:The malaria-causing blood stage of Plasmodium falciparum requires extracellular pantothenate for proliferation. The parasite converts pantothenate into coenzyme A (CoA) via five enzymes, the first being a pantothenate kinase (PfPanK). Multiple antiplasmodial pantothenate analogues, including pantothenol and CJ-15,801, kill the parasite by targeting CoA bio-synthesis/utilisation. Their mechanism of action, however, remains unknown. Here, we show that parasites pressured with pantothenol or CJ-15,801 become resistant to these analogues. Whole-genome sequencing revealed mutations in one of two putative PanK genes (Pfpank1) in each resistant line. These mutations significantly alter PfPanK activity, with two conferring a fitness cost, consistent with Pfpank1 coding for a functional PanK that is essential for normal growth. The mutants exhibit a different sensitivity profile to recently-described, potent, antiplasmodial pantothenate analogues, with one line being hypersensitive. We provide evidence consistent with different pantothenate analogue classes having different mechanisms of action: some inhibit CoA biosynthesis while others inhibit CoA-utilising enzymes.
Total 5 results found
Copyright 2006-2020 © Xi'an Jiaotong-Liverpool University 苏ICP备07016150号-1 京公网安备 11010102002019号