Pantothenic acid biosynthesis in the parasite Toxoplasma gondii: a target for chemotherapy.
Antimicrob Agents Chemother. 2014 Jul 21;
Authors: Mageed SN, Cunningham F, Hung AW, Silvestre HL, Wen S, Blundell TL, Abell C, McConkey GA
Toxoplasma gondii is a major food pathogen and neglected parasitic infection that causes eye disease, birth defects, and fetal abortion and plays a role as an opportunistic infection in AIDS. In this study, we investigated pantothenic acid (vitamin B5) biosynthesis in T. gondii. Genes encoding the full repertoire of enzymes for pantothenate synthesis and subsequent metabolism to Coenzyme A were identified and are expressed in T. gondii. A panel of inhibitors developed to target Mycobacterium tuberculosis pantothenate synthetase were tested and found to exhibit a range of inhibitions of growth of T. gondii. Two inhibitors exhibited lower effective concentrations than the current toxoplasmosis drug pyrimethamine. The inhibition was specific for the pantothenate pathway as the effect of the pantothenate synthetase inhibitors was abrogated by supplementation with pantothenate. Hence, T. gondii encodes and expresses the enzymes for pantothenate synthesis and this pathway is essential for parasite growth. These promising findings increase our understanding of growth and metabolism in this important parasite and highlight pantothenate synthetase as a new drug target.
PMID: 25049241 [PubMed - as supplied by publisher]
An integrated computational approach can classify VHL missense mutations according to risk of clear cell Renal carcinoma.
Hum Mol Genet. 2014 Jun 26;
Authors: Gossage L, Pires DE, Olivera-Nappa A, Asenjo J, Bycroft M, Blundell TL, Eisen T
Mutations in the von Hippel-Lindau (VHL) gene are pathogenic in VHL disease, congenital polycythaemia and clear cell renal carcinoma. pVHL forms a ternary complex with Elongin C and Elongin B, critical for pVHL stability and function, which interacts with Cullin-2 and RING-box protein 1 to target Hypoxia-inducible factor for polyubiquitination and proteasomal degradation. We describe a comprehensive database of missense VHL mutations linked to experimental and clinical data. We use predictions from in silico tools to link the functional effects of missense VHL mutations to phenotype. The risk of clear cell renal carcinoma in VHL disease is linked to the degree of destabilisation resulting from missense mutations. An optimised binary classification system (Symphony), which integrates predictions from five in silico methods, can predict the risk of ccRCC associated with VHL missense mutations with high sensitivity and specificity. We use Symphony to generate predictions for risk of ccRCC for all possible VHL missense mutations and present these predictions, in association with clinical and experimental data, in a publically available, searchable web server.
PMID: 24969085 [PubMed - as supplied by publisher]
DUET: a server for predicting effects of mutations on protein stability using an integrated computational approach.
Nucleic Acids Res. 2014 May 14;
Authors: Pires DE, Ascher DB, Blundell TL
Cancer genome and other sequencing initiatives are generating extensive data on non-synonymous single nucleotide polymorphisms (nsSNPs) in human and other genomes. In order to understand the impacts of nsSNPs on the structure and function of the proteome, as well as to guide protein engineering, accurate in silicomethodologies are required to study and predict their effects on protein stability. Despite the diversity of available computational methods in the literature, none has proven accurate and dependable on its own under all scenarios where mutation analysis is required. Here we present DUET, a web server for an integrated computational approach to study missense mutations in proteins. DUET consolidates two complementary approaches (mCSM and SDM) in a consensus prediction, obtained by combining the results of the separate methods in an optimized predictor using Support Vector Machines (SVM). We demonstrate that the proposed method improves overall accuracy of the predictions in comparison with either method individually and performs as well as or better than similar methods. The DUET web server is freely and openly available at http://structure.bioc.cam.ac.uk/duet.
PMID: 24829462 [PubMed - as supplied by publisher]
Protein-protein interactions as druggable targets: recent technological advances.
Curr Opin Pharmacol. 2013 Oct;13(5):791-6
Authors: Higueruelo AP, Jubb H, Blundell TL
Classical target-based drug discovery, where large chemical libraries are screened using inhibitory assays for a single target, has struggled to find ligands that inhibit protein-protein interactions (PPI). Nevertheless, in the past decade there have been successes that have demonstrated that PPI can be useful drug targets, and the field is now evolving fast. This review focuses on the new approaches and concepts that are being developed to tackle these challenging targets: the use of fragment based methods to explore the chemical space, stapled peptides to regulate intracellular PPI, alternatives to competitive inhibition and the use of antibodies to enable small molecule discovery for these targets.
PMID: 23735579 [PubMed - indexed for MEDLINE]