Journal of Stem Cell Research & Therapy

Identification and characterisation of cyclic peptide inhibitors of Ras/p110α and Ras/Raf protein complexes

4^th International Conference and Exhibition on Cell & Gene Therapy

August 10-12, 2015 London, UK

Mohamed Ismail and Julian Downward

Scientific Tracks Abstracts: J Stem Cell Res Ther

Abstract:

Ras proteins belong to the GTPase superfamily of proteins; they consist of HRas, NRas and KRas. Ras is involved in various
cellular functions cell growth, proliferation, differentiation and activation. Ras proteins behave as molecular switches, and
their activity is GTP dependent. Ras-GTP promotes effector binding and activates downstream signalling such as PI3K and
Raf pathways. Oncogenic Ras mutations have been found almost 20% of cancers, with KRas being the most highly mutated.
These oncogenic mutations prevent the hydrolysis of GTP to GDP resulting in a constant active state of Ras that persistently
activates downstream signalling. There have been many efforts to develop inhibitors that interrupt interaction of oncogenic
Ras to effector kinases such as PI3K and Raf in order to block their constant activated pathways. These inhibitors however have
limited success due to either their weak binding affinity for Ras, or the lack of specificity to Ras mutants. Here, in collaboration
with Ali Tavassoli’s lab in Southampton University, we are applying a new approach for discovering inhibitors of Ras mutants.
This approach combines two methodologies: The “split-intein cyclisation of peptides and proteins” (SICLOPPS), for producing
random cyclic peptides in vivo; and a bacterial reverse two-hybrid system (RTHS), that is used to screen for successful inhibitors.
SICLOPPS has the capacity to produce millions of random cyclic peptides, which significantly increases the chances of finding
suitable inhibitors, to interrupt protein complexes. At the same time RTHS provides a time efficient and effective technique to
screen such a high number of peptides.

Biography :

Mohamed Ismail completed PhD at the International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, 2003-2007. From 2008-2014 he worked
as a Postdoctoral Scientist at The National Institute for Medical Research (NIMR), Medical Research Council (MRC), London, UK. From 2014-present, he is
working as a Research Fellow at Cancer Research UK (CRUK), London Research Institute (LRI), London, UK.