Synthesis of Unprecedented Sulfonylated Phosphono‐<i>exo</i>‐Glycals Designed as Inhibitors of the Three Mycobacterial Galactofuranose Processing Enzymes

Frédéric, Christophe J.-M.; Tikad, Abdellatif; Fu, Jian; Pan, Weidong; Zheng, Ruixiang Blake; Koizumi, Akihiko; Xue, Xiaochao; Lowary, Todd L.; Vincent, Stéphane

doi:10.1002/chem.201603161

Cited by 22 publications

(14 citation statements)

References 91 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…UGM is essential for Mycobacterium tuberculosis [8] and a virulence factor in A. fumigatus [12]. Its role in virulence and the absence of a UGM homolog in mammals has spurred the search and development of inhibitors against this enzyme [21,22]. Several methods have been used to screen inhibitors of UGMs mainly from bacterial sources [23].…”

Section: Discussionmentioning

confidence: 99%

Identification of eukaryotic UDP-galactopyranose mutase inhibitors using the ThermoFAD assay

Campo

Eckshtain-Levi

Sobrado

2017

Biochemical and Biophysical Research Communications

View full text Add to dashboard Cite

Aspergillus fumigatus is a human pathogen responsible for deadly infections in immune-compromised patients. A potential strategy for treating A. fumigatus infections is by targeting the biosynthesis of cell wall components, such as galactofuranase, which is absent in humans. Galactofuranose biosynthesis is initiated by the flavoenzyme UDP-galactopyranose mutase (UGM), which converts UDP-galactopyranose (UDP-Galp) to UDP-galactofuranose (UDP-Galf). UGM requires the reduced form of the flavin for activity, which is obtained by reacting with NADPH. We aimed to identify inhibitors of UGM by screening a kinase inhibitor library using ThermoFAD, a flavin fluorescence thermal shift assay. The screening assay identified flavopiridol as a compound that increased the melting temperature of A. fumigatus UGM. Further characterization showed that flavopiridol is a non-competitive inhibitor of UGM and docking studies suggest that it binds in the active site. This compound does not inhibit the prokaryotic UGM from Mycobacteria tuberculosis.

show abstract

Section: Discussionmentioning

confidence: 99%

Identification of eukaryotic UDP-galactopyranose mutase inhibitors using the ThermoFAD assay

Campo

Eckshtain-Levi

Sobrado

2017

Biochemical and Biophysical Research Communications

View full text Add to dashboard Cite

show abstract

“…Because this form of galactose is not present in humans [74,75], these enzymes were repeatedly proposed as potential targets for the development of novel antituberculosis drugs. An attractive option would be to target all three enzymes with one inhibitor, which appears to be relevant owing to a putative common transition state, as recently proposed by Vincent and colleagues [76] (Figure 7). Transition states structures of UGM, GlfT1, and GlfT2.…”

Section: Search For Inhibitors Of the Galactan Pathwaymentioning

confidence: 99%

“…The UGM catalytic mechanism (Figure 3) indicates the possible presence of an oxocarbenium ion in the transition state. Hence, Pinto and co-workers synthesized two mimics carrying a permanent positive charge, 2-deoxy d-arabinitol derivatives containing sulfonium and selenonium ions with an appended polyhydroxylated side chain ( [76]. However, none of these molecules appeared to efficiently inhibit UGM from M. tuberculosis.…”

Section: Ugm Assays and Inhibitorsmentioning

confidence: 99%

Biosynthesis of Galactan in Mycobacterium tuberculosis as a Viable TB Drug Target?

et al. 2020

View full text Add to dashboard Cite

While target-based drug design has proved successful in several therapeutic areas, this approach has not yet provided compelling outcomes in the field of antibacterial agents. This statement remains especially true for the development of novel therapeutic interventions against tuberculosis, an infectious disease that is among the top ten leading causes of death globally. Mycobacterial galactan is an important component of the protective cell wall core of the tuberculosis pathogen and it could provide a promising target for the design of new drugs. In this review, we summarize the current knowledge on galactan biosynthesis in Mycobacterium tuberculosis, including landmark findings that led to the discovery and understanding of three key enzymes in this pathway: UDP-galactose mutase, and galactofuranosyl transferases GlfT1 and GlfT2. Moreover, we recapitulate the efforts aimed at their inhibition. The predicted common transition states of the three enzymes provide the lucrative possibility of multitargeting in pharmaceutical development, a favourable property in the mitigation of drug resistance. We believe that a tight interplay between target-based computational approaches and experimental methods will result in the development of original inhibitors that could serve as the basis of a new generation of drugs against tuberculosis.

show abstract

“…Recently, several attempts to develop GlfT2 inhibitors have been undertaken. The focus has been put on donor and acceptor analogues . Also, iminosugar analogues were used as mimetics of a proposed model of the transition state of the glycosyltransferase reaction .…”

Section: Introductionmentioning

confidence: 99%

“…The focus has been put on donor and acceptora nalogues. [22][23][24][25][26][27][28][29] Also, iminosugar analogues were used as mimetics of ap roposed model of the transition state of the glycosyltransferase reaction. [30] However, they have in-hibitory activity in the millimolar range,a nd to date, no inhibitor of GlfT2 with sufficient potential has been identified.…”

Section: Introductionmentioning

confidence: 99%

How Mycobacterium tuberculosis Galactofuranosyl Transferase 2 (GlfT2) Generates Alternating β‐(1–6) and β‐(1–5) Linkages: A QM/MM Molecular Dynamics Study of the Chemical Steps

Janoš

Kozmon

Tvaroŝka

et al. 2018

Chemistry A European J

View full text Add to dashboard Cite

Mycobacterium tuberculosis features a unique cell wall that protects the bacterium from the external environment. Disruption of the cell wall assembly is a promising direction for novel anti-tuberculotic drugs. A key component of the cell wall is galactan, a polysaccharide chain composed of galactofuranose (Galf) units connected by alternating β-(1-5) and β-(1-6) linkages. The majority of the galactan chain is biosynthesized by a bifunctional enzyme-galactofuranosyl transferase 2 (GlfT2). GlfT2 catalyzes two reactions: the formation of β-(1-5) and β-(1-6) linkages. It was suggested that the enzyme acts through a processive mechanism until it adds 30-35 Galf units in a single active site. We applied a QM/MM string method coupled with ab initio molecular dynamics simulations to study the two reactions catalyzed by GlfT2. We showed that both reactions proceed very similarly and feature similar transition-state structures. We also present novel information about the ring puckering behavior of the five-membered furanose ring during the glycosyltransferase reaction and a calculated transition-state structure with galactose in a furanose form that may be used as a guide for the rational design of very specific and extremely potent inhibitors, that is, transition-state analogues, for GlfT2. Due to the absence of a furanose form of galactose in humans, transition-state-analogous inhibitors represent an attractive scaffold for the development of novel antibacterial drugs.

show abstract

Synthesis of Unprecedented Sulfonylated Phosphono‐exo‐Glycals Designed as Inhibitors of the Three Mycobacterial Galactofuranose Processing Enzymes

Cited by 22 publications

References 91 publications

Identification of eukaryotic UDP-galactopyranose mutase inhibitors using the ThermoFAD assay

Identification of eukaryotic UDP-galactopyranose mutase inhibitors using the ThermoFAD assay

Biosynthesis of Galactan in Mycobacterium tuberculosis as a Viable TB Drug Target?

How Mycobacterium tuberculosis Galactofuranosyl Transferase 2 (GlfT2) Generates Alternating β‐(1–6) and β‐(1–5) Linkages: A QM/MM Molecular Dynamics Study of the Chemical Steps

Contact Info

Product

Resources

About