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ESR-9 Inhibitors of the mRNA capping machinery of Alphaviruses (AMU)

Project description
Alphaviruses are emerging arboviruses which are known to possess a unique capping mechanism carried out by the viral non structural protein nsP1. The enzyme harbours methyltransferase (MTase) and nsP1 guanylylation (GT) activities catalysing the transfer of the methyl group from S-Adenosylmethionine (AdoMet) to a GTP molecule followed by the formation of a m7GMP-nsP1 , the substrate for the RNA capping reaction. Because of its unconventional mechanism, alphavirus mRNA capping is an attractive target for the design of specific inhibitors. In the lab, we have recently characterized the biochemical activities of Venezuelan equine encephalitis virus (VEEV) nsP1. To do so, we have developed enzymatic assays uncoupling the different reaction steps catalysed by nsP1 and used reference capping inhibitors. The ESR will screen series of potential inhibitors by HT enzymatic assays. The most potent ones will be tested on infected cells in order to select viral escape mutants and understand their mechanism of action. This project will foster the development of novel molecules with antiviral activity as well as contribute to a better understanding of nsP1 regulation in the capping process.
Methods used: biochemistry, molecular biology, enzymology, basic structural/biophysical methods, cell culture.

The Network
This PhD position is part of the European training network ANTIVIRALS (www.antivirals-etn.eu). The candidate will benefit from the ANTIVIRALS network, which includes regular (scientific) network meetings and training in research methodology and complementary skills. This research project offers unique opportunities for establishing a broad and international scientific network with partners from the academic and industrial sector. The research project is performed in close collaboration with and partly at the premises of other institutions of the ANTIVIRALS network.

Host institute
The AFMB laboratory (UMR 7257, affiliated to the CNRS, and the Aix Marseille Université, France) is a research centre in structural biology, organized in two research Departments supported by a state-of-the- art technical platform and various services which counts approximately 84 persons, out of which 40 hold a permanent position. The AFMB laboratory is a component of the federative structure “Infectiopôle, du Malade à la Molécule” and has made important contributions to the field of structural biology through several French and European programs aimed at implementing a multidisciplinary approach to document the architectures of proteins and their functional implications. The lab is at the forefront of structural proteomics and has developed an operating structural proteomics platform "from gene to structure", which includes domain design, parallel and robotized cloning, expression, purification and crystallization steps of targets of interest. The team "Viral replicase: structure, mechanism and drug-design" characterizes enzymes and proteines from emerging viruses involved in the replication of their genome and transcription of their messenger RNAs.

Research of the ESR will be embedded in the Doctoral School of Aix marseille University, facilitating collaborations with other researchers involved in Infectious diseases and Microbiology in the broad Marseille area.

Vacancy closed