Synthesis and biological evaluation of nonionic substrate mimics of UDP-Galp as candidate inhibitors of UDP galactopyranose mutase (UGM)

Kuppala, Ramakrishna; Borrelli, Silvia; Slowski, Kathryn; Sanders, D.A.R.; Kartha, K. P. Ravindranathan; Pinto, B. Mario

doi:10.1016/j.bmcl.2015.03.006

Cited by 11 publications

(10 citation statements)

References 16 publications

(11 reference statements)

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“…To confirm the SAR previously established and further study the binding mode of flavonoids, luteolin ( 4 ) was subjected to docking simulations. All modeling calculations were performed by using two different Mt UGM crystal structures in two distinct conformations: a closed form (PDB code: 4RPH) and an opened form (PDB code: 1V0J). The major difference between the two structures is the conformation of the mobile loop (Gln167–Arg184), which is directly linked to substrate binding.…”

Section: Resultsmentioning

confidence: 99%

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Natural and Synthetic Flavonoids as Potent Mycobacterium tuberculosis UGM Inhibitors

Villaume

N’Go

et al. 2017

Chemistry A European J

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This study reports a novel class of inhibitors of uridine 5'-diphosphate (UDP) galactopyranose mutase (UGM) derived from a screening of natural products. This enzyme is an essential biocatalyst involved in the cell wall biosynthesis of Mycobacterium tuberculosis. Flavonoids are potent inhibitors of UGM. The synthesis of novel methylated flavonoids allowed a structure-activity relationship analysis to be performed and which functional groups and structural elements were required for UGM inhibition could be determined. The binding mode of one of the best inhibitors was found to be noncompetitive. Docking simulations indicated that this molecule was likely to bind UGM in its open conformation, in a cavity recently identified as a "druggable" pocket. Importantly, two of the best inhibitors of the M. tuberculosis UGM displayed moderate activity against whole M. tuberculosis cells. This study reports the first natural products that act as inhibitor of UGM. Given the importance of natural products in medicinal chemistry, these results create new opportunities for the discovery of new antitubercular agents.

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Section: Resultsmentioning

confidence: 99%

“…Several approaches have been adopted to design UGM inhibitors ,. Among them, mechanism‐based inhibitors,,,, substrate analogues inhibitors,, and heterocyclic molecules obtained from screening of chemical libraries or virtual screening have also emerged.…”

Section: Introductionmentioning

confidence: 99%

Natural and Synthetic Flavonoids as Potent Mycobacterium tuberculosis UGM Inhibitors

Villaume

N’Go

et al. 2017

Chemistry A European J

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“…16,18–20,22,24–30 Though inhibitors have emerged, 18–20,31 few have been shown to function against microbial pathogens. We previously developed a fluorescence polarization (FP) assay to identify competitive UGM inhibitors.…”

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confidence: 99%

Virtual Screening for UDP-Galactopyranose Mutase Ligands Identifies a New Class of Antimycobacterial Agents

et al. 2015

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Galactofuranose (Galf) is present in glycans critical for the virulence and viability of several pathogenic microbes, including Mycobacterium tuberculosis, yet the monosaccharide is absent from mammalian glycans. Uridine 5′-diphosphate-galactopyranose mutase (UGM) catalyzes the formation of UDP-Galf, which is required to produce Galf-containing glycoconjugates. Inhibitors of UGM have therefore been sought, both as antimicrobial leads and as tools to delineate the roles of Galf in cells. Obtaining cell permeable UGM probes by either design or high throughput screens has been difficult, as has elucidating how UGM binds small molecule, noncarbohydrate inhibitors. To address these issues, we employed structure-based virtual screening to uncover new inhibitor chemotypes, including a triazolothiadiazine series. These compounds are among the most potent antimycobacterial UGM inhibitors described. They also facilitated determination of a UGM–small molecule inhibitor structure, which can guide optimization. A comparison of results from the computational screen and a high-throughput fluorescence polarization (FP) screen indicated that the scaffold hits from the former had been evaluated in the FP screen but missed. By focusing on promising compounds, the virtual screen rescued false negatives, providing a blueprint for generating new UGM probes and therapeutic leads.

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“…Major components are lipidated polysaccharides, like the mycolyl−arabinogalactan complex, essentially composed of galactofuranose (Gal f ) and arabinofuranose (Ara f ) [ 205 ]. In recent years, numerous efforts have been done to develop inhibitors of UDP-galactopyranose mutase (UGM), an enzyme essential for the growth and survival of this mycobacterium [ 206 , 207 , 208 , 209 , 210 , 211 , 212 ]. Among the vital cell envelope components, phosphatidylinositol mannosides (PIMs) and their corresponding hyper-mannosylated derivatives (lipomannans and lipoarabinomannans) are noncovalently anchored to the plasma membrane and the outer capsule via their lipid chains.…”

Section: Mycobacterium Tuberculosismentioning

confidence: 99%

Recent Advances in the Synthesis of Glycoconjugates for Vaccine Development

2018

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During the last decade there has been a growing interest in glycoimmunology, a relatively new research field dealing with the specific interactions of carbohydrates with the immune system. Pathogens’ cell surfaces are covered by a thick layer of oligo- and polysaccharides that are crucial virulence factors, as they mediate receptors binding on host cells for initial adhesion and organism invasion. Since in most cases these saccharide structures are uniquely exposed on the pathogen surface, they represent attractive targets for vaccine design. Polysaccharides isolated from cell walls of microorganisms and chemically conjugated to immunogenic proteins have been used as antigens for vaccine development for a range of infectious diseases. However, several challenges are associated with carbohydrate antigens purified from natural sources, such as their difficult characterization and heterogeneous composition. Consequently, glycoconjugates with chemically well-defined structures, that are able to confer highly reproducible biological properties and a better safety profile, are at the forefront of vaccine development. Following on from our previous review on the subject, in the present account we specifically focus on the most recent advances in the synthesis and preliminary immunological evaluation of next generation glycoconjugate vaccines designed to target bacterial and fungal infections that have been reported in the literature since 2011.

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Synthesis and biological evaluation of nonionic substrate mimics of UDP-Galp as candidate inhibitors of UDP galactopyranose mutase (UGM)

Cited by 11 publications

References 16 publications

Natural and Synthetic Flavonoids as Potent Mycobacterium tuberculosis UGM Inhibitors

Natural and Synthetic Flavonoids as Potent Mycobacterium tuberculosis UGM Inhibitors

Virtual Screening for UDP-Galactopyranose Mutase Ligands Identifies a New Class of Antimycobacterial Agents

Recent Advances in the Synthesis of Glycoconjugates for Vaccine Development

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