title: UDP-galactopyranose mutase, a potential drug target against human pathogenic nematode Brugia malayi.
abstract: Lymphatic filariasis, a vector-borne neglected tropical disease affects millions of population in tropical and subtropical countries. Vaccine unavailability and emerging drug resistance against standard antifilarial drugs necessitate search of novel drug targets for developing alternate drugs. Recently, UDP-galactopyranose mutases (UGM) have emerged as a promising drug target playing an important role in parasite virulence and survival. This study deals with the cloning and characterization of Brugia malayi UGM and further exploring its antifilarial drug target potential. The recombinant protein was actively involved in conversion of UDP-galactopyranose (substrate) to UDP-galactofuranose (product) revealing Km and Vmax to be ∼51.15 μM and ∼1.27 μM/min, respectively. The purified protein appeared to be decameric in native state and its 3D homology modeling using Aspergillus fumigatus UGM enzyme as template revealed conservation of active site residues. Two specific prokaryotic inhibitors (compounds A and B) of the enzyme inhibited B. malayi UGM enzymatic activity competitively depicting Ki values ∼22.68 and ∼23.0 μM, respectively. These compounds were also active in vitro and in vivo against B. malayi The findings suggest that B. malayi UGM could be a potential antifilarial therapeutic drug target.
authors.affiliation: Academy of Scientific and Innovative Research (AcSIR), Anusandhan Bhawan, New Delhi-110001, India Division of Parasitology, CSIR-Central Drug Research Institute, BS 10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow-226031, India.
authors.forename: Sweta
authors.initials: S
authors.lastname: Misra
authors.affiliation: Academy of Scientific and Innovative Research (AcSIR), Anusandhan Bhawan, New Delhi-110001, India Division of Pharmacokinetics and Metabolism, CSIR-Central Drug Research Institute, BS 10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow-226031 (U.P.), India.
authors.forename: Guru R
authors.initials: GR
authors.lastname: Valicherla
authors.affiliation: Academy of Scientific and Innovative Research (AcSIR), Anusandhan Bhawan, New Delhi-110001, India Division of Parasitology, CSIR-Central Drug Research Institute, BS 10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow-226031, India.
authors.lastname: Mohd Shahab
authors.affiliation: Academy of Scientific and Innovative Research (AcSIR), Anusandhan Bhawan, New Delhi-110001, India Division of Parasitology, CSIR-Central Drug Research Institute, BS 10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow-226031, India.
authors.forename: Jyoti
authors.initials: J
authors.lastname: Gupta
authors.affiliation: Academy of Scientific and Innovative Research (AcSIR), Anusandhan Bhawan, New Delhi-110001, India Division of Pharmacokinetics and Metabolism, CSIR-Central Drug Research Institute, BS 10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow-226031 (U.P.), India.
authors.forename: Jiaur R
authors.initials: JR
authors.lastname: Gayen
authors.affiliation: Academy of Scientific and Innovative Research (AcSIR), Anusandhan Bhawan, New Delhi-110001, India Division of Parasitology, CSIR-Central Drug Research Institute, BS 10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow-226031, India shailja_cdri@rediffmail.com.
authors.forename: Shailja
authors.initials: S
authors.lastname: Misra-Bhattacharya
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000871:Anthelmintics / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D017178:Brugia malayi / Q000145:classification / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics; D003001:Cloning, Molecular; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D005368:Filariasis / Q000188:drug therapy / Q000469:parasitology; D015870:Gene Expression; D006801:Humans; D019751:Intramolecular Transferases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008024:Ligands; D008958:Models, Molecular; D021261:Parasitic Sensitivity Tests; D010802:Phylogeny; D011487:Protein Conformation; D055503:Protein Multimerization; D017422:Sequence Analysis, DNA
chemical_list: D000871:Anthelmintics; D004791:Enzyme Inhibitors; D008024:Ligands; D019751:Intramolecular Transferases; C098051:UDP-galactopyranose mutase
keywords: Brugia malayi; UDP-galactopyranose mutase; high- performance liquid chromatography, in vitro and in vivo antifilarial efficacy, drug target; size exclusion chromatography