StapPep · Stapled peptide analogues as inhibitors of the CCR4-NOT complex to regulate the mRNA degradation

Stapled peptide analogues as inhibitors of the CCR4-NOT complex to regulate the mRNA degradation

Human body functions are controlled by several biomolecules (eg. DNA, RNA, proteins and lipids). Malfunction of any of these biomolecules is responsible for numerous diseases including cancers. Among these biomolecules, RNA has gained a significant attention recently as a therapeutic target due to its evolutionary role in gene regulations. In the gene regulation process, RNA seldom works as an individual entity but rather associated with several protein-protein complexes (PPCs) and these complexes play a key role in mRNA maturation. Almost all mRNA contains a stretch of adenosine (called poly(A) tail) at the 3’ end which plays an important role in mRNA stability and translation process. Typically, mRNA undergoes different post-transcriptional modifications and deadenylation is the key post-transcriptional event in which the shortening of the poly(A) tail at the 3’ end of mRNA occurs and therefore influences the overall mRNA stability. Deadenylation is often regulated by different PPCs and dysregulation of any of these complexes severely impaired this process. In fact, deadenylation process is considered to be the surveillance mechanism for the cell and uncontrolled deadenylation could drives the cell to the oncogenic state. In many cancer cells shortening of poly(A) tail has been found due to the non-specific deadenylation event. Therefore, chemical modulators that can regulate the deadenylation process have immense therapeutic importance. The major focus of the ‘StapPep’ project is to stabilize mRNA containing poly(A) tail by identifying suitable inhibitors against CCR4-NOT complex which is a crucial player of the mRNA degradation. Therefore, the key object of this project is to develop peptidic modulators to inhibit the mRNA deadenylation process in target specific manner by directly inhibiting the activity of CCR4-NOT complex. This approach is unique in the sense that only weak inhibitors without any cellular activities were reported. Moreover, the better stability, larger surface area, versatile side-chain functionalities and low cytotoxicity are advantageous for peptide drugs over the traditional small molecules. We anticipate that the current strategy would open a new way of tackling cancer by modulating the mRNA stability and thus revolutionize the therapeutics invention for the future cancer treatments.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз