Research Projects

Tuberculosis (TB), caused by Mycobacterium tuberculosis(Mtb), remains one of the world’s deadliest infectious diseases. A major challenge in TB control lies in Mtb’s ability to subvert the host immune system to establish its niche, proliferate and disseminate or to evade the immune system and enter into latency until favourable conditions. M.tb employs several virulence factors and engages plethora of host proteins for its survival. ESAT-6 (Early Secreted Antigenic Target-6), is an important virulence factor secreted by the ESX-1 secretion system of Mtb, which by disrupting the phagosomal membrane, promotes cytosolic escape, and modulates immune responses. ESAT-6 can also suppress cytokine production, and downregulate antigen presentation. Additionally ESAT-6 through its interaction with ENO1, enhances macrophage glycolysis and thereby promotes mycobacterial persistence. ESAT6 till date has been used as a diagnostic marker or vaccine candidate but not as a therapeutic target, wherein its targeted intracellular degradation would pathogenic progression and induce rapid lysosomal transfer mediated Mtb elimination. Recently, peptidomimetics targeting protein-protein interactions have emerged as a promising class of therapeutics for undruggable or non-enzymatic proteins since these synthetic molecules mimic natural peptides but offer better stability, specificity, and cellular entry. Synthetic peptide-based drugs can precisely target pathogenic proteins. Building on this, PROteolysis TArgeting Chimeras (PROTACs) have been designed to degrade disease-related proteins via the ubiquitin-proteasome system. Presently peptide-based PROTACs (p-PROTACs) are being used for non-enzymatic proteins such as Akt and BCR-ABL in context of cancer. Inspired by these efforts, this project proposes a novel p-PROTAC to induce proteasomal degradation of intracellular ESAT-6. A synthetic peptidomimetic termed "ESAT-6 warhead" which mimics the ESAT-6 binding sequences of ENO1 when linked to a degron known to recruit host E3 ligases would effectively induce ubiquitination and concomitant proteasomal degradation of ESAT-6. Encapsulation of the ESAT-6 warhead along with glycolytic suppressor inside surface functionalized liposomes would effectively induce rapid lysosomal transfer mediated elimination of the infected M.tb. The dual strategy of degrading ESAT-6 and partially supressing ENO1 activity would not only facilitate M.tb elimination but can also be effective against other infections. This strategy integrates computational modeling, peptide design, structural biology, and nanotechnology, to support virulence factor targeted alternative precision therapeutics to address intracellular infections and reduce drug resistance menace