+1 (629)348-3199Modified PAS analogues making PAS great again
9th International Conference on COPD and Lung Health
September 13, 2022 | Webinar
Pooja Hegde
University of Minnesota, USA
Posters & Accepted Abstracts : Int J Respir Med
Abstract:
Tuberculosis (TB) is one of the deadliest infectious disease resulting in nearly 1.5 million deaths annually and infecting nearly one-quarter of the population. Para-aminosalicylic acid (PAS), an important second-line agent for treating drugresistant mycobacteria, has low bioavailability and rapid clearance that necessitate high daily doses of up to 12 grams/ day, which in turn causes severe gastrointestinal disturbances by disruption of gut microbiota and host epithelial cells. In this project we aim to improve the bioavailability of PAS, while retaining its anti-mycobacterial activity. We have developed a series of prodrugs that substantially increase the oral bioavailability, which prevents intestinal accumulation as well as undesirable bioactivation by the gut microbiome to non-natural folate species that exhibit cytotoxicity. The conceptually simple prodrug approach does not address the intrinsic rapid clearance of PAS by N-acetyltransferase (NAT); thus, we have also designed analogues of the PAS scaffold to lower clearance of PAS enzymes by sterically blocking N-acetylation and electronic deactivation of the para-amino group. Combination of these dual approaches together may provide a next-generation PAS drug with substantially higher oral exposure to prevent adverse reactions and development of resistance.
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