Abstract:
RNA provides an inviting target for pharmaceutical intervention in both infectious and chronic diseases, but drug-like molecules with sufficient potency for successful clinical application remain to be identified. We have developed a class of constrained peptides that bind RNA and used structure-based drug design to optimize their activity in targeting the interaction between the HIV-1 transactivator protein Tat and its response element TAR, which plays an essential role in viral replication and the emergence of the virus from latency. The most potent inhibitor has low pM binding activity, discriminate >1,000 fold between even closely related RNAs, have no cytotoxicity and inhibit viral replication with potency comparable to current FDA-approved antivirals. The same design strategy is applied to discover new inhibitors of microRNA maturation that down regulate the expression of oncogenic microRNAs. We have used peptide and protein design to engineer activities that inhibit microRNA expression. We investigate whether the inhibition of the biogenesis of specific microRNAs can have pharmaceutical benefits and pursue the development of potent inhibitors of microRNA function.