Targeting Nucleases via Transition State Mimicry
Lead Research Organisation:
University of Oxford
Department Name: Oxford Chemistry
Abstract
Nucleases, enzymes that cleave nucleic acid phosphodiester bonds, are of fundamental biological importance and cornerstone reagents in molecular biology. They are, however, remarkably under-represented as drug targets, e.g. compared to kinases as there are lack of starting points for selective nuclease inhibition. This project aims to design and synthesis nuclease inhibitors based on knowledge on mechanistic knowledge-in particular to target transition state analogues (TSA) of phosphodiester hydrolysis. The nucleases to be targeted have a metallo beta-lactamase (MBL) fold and are involved in RNA processing-other family members catalysing lactam hydrolysis are amenable to the TSA approach (e.g. cyclic boronates). The project will synergise GSK medicinal chemistry and Oxford chemical biology expertise providing training at the chemistry-biology interface which is a 'Grow Research Area Action'. This project falls within the EPSRC Chemical Biology and Biological Chemistry research area.
| Description | Formaldehyde (HCHO), a highly reactive electrophile, is both a human metabolite and a carcinogen above threshold levels. As HCHO is produced during enzymatic reactions in the human cell, a scavenging role for the N-terminal end of proteins was hypothesised. Here, it is shown that the N-terminus of H2B (bearing an N-terimal proline) has an exceptional susceptibility to reactions with HCHO, whilst it doesn't react with similar compounds. The resulting HCHO derived adduct is a fused 5,5-bicycle which is chemically very stable. These results imply that N-terminal prolines on proteins may act as potential sink for genotoxic HCHO. On another project, we investigate N-terminal cysteines which also react readiliy with HCHO to form stable adducts. It is conceivable that these reactions inhibit enzymatic activities of proteins that rely on N-terminal cysteines. |
| Exploitation Route | As this is a basic science project, it is important for other researchers to know that N-terminal prolines and cysteines can be influenced by HCHO, as HCHO is often used as additives (e.g. in vaccines). |
| Sectors | Chemicals,Healthcare,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology |