# NIH grant: Defining Molecular Targets and Optimizing Novel Small Molecules for Schistosomiasis Therapy (1K99AI201746-01) — retained record

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NIH grant 1K99AI201746-01: Defining Molecular Targets and Optimizing Novel Small Molecules for Schistosomiasis Therapy
Institute: {'code': 'AI', 'abbreviation': 'NIAID', 'name': 'National Institute of Allergy and Infectious Diseases', 'admin_org_id': '12500003', 'admin_funding_url': ''}. PI: Karol Rogelle Karagdag Francisco. Award: $184693.
Start: 2026-08-21T00:00:00.
Project Summary
 Schistosomiasis is a neglected tropical disease (NTD) that affects 250 million people worldwide, with another
700 million at risk. This chronic and debilitating disease perpetuates poverty by impairing health and limiting
productivity. Despite its global burden, treatment relies on a single drug, praziquantel (PZQ), which has major
limitations, including poor activity against juvenile worms, extensive first-pass metabolism, low oral
bioavailability, and the looming threat of resistance due to mass drug administration. These challenges
underscore the urgent need for new therapies with novel mechanisms of action (MOAs). To address this need,
I designed and synthesized a series of thiophenyl pyrimidine (TPP) analogs with potent activity against the
laboratory model schistosome, Schistosoma mansoni. These compounds induce a rapid and permanent
paralysis of both adult and juvenile worms, potentially offering a broader spectrum of activity than PZQ. TPPs
are derived from small molecules that engage microtubules (MTs), but unlike their progenitors, the anti-
schistosomal analogs do not engage MTs and are non-cytotoxic. To investigate their MOA, I designed and
synthesized a TPP-based photoaffinity labeling (PAL) probe, which confirmed that Schistosoma MTs are not the
target. Iterative structure-activity relationship studies further identified a lead candidate with potency comparable
to PZQ, but further optimization is needed to achieve a preclinical candidate with the physicochemical properties
for oral cure.
 In the mentored K99 phase, I will (Aim 1a) evaluate the in vitro activity of TPPs across all three medically
important Schistosoma species, (Aim 1b) characterize the metabolic profiles of TPP analogs, and (Aim 1c)
determine their cellular localization using a fluorescent probe. For both the K99 and independent R00 phases,
I will (Aim 2a) identify TPP-binding proteins through chemoproteomics, (Aim 2b) integrate chemoproteomics with
bioinformatics to elucidate MOA, and (Aim 2c) apply AI-based structure prediction and homology modeling to
explore binding sites and guide target-based design. Additionally, in both phases, I will (Aim 3a) design and
synthesize TPP analogs to improve pharmacokinetics, (Aim 3b) evaluate plasma PK of lead compounds, and
(Aim 3c) conduct efficacy studies in a murine model of S. mansoni infection. To enable the above studies, I will
receive training in schistosome biology, metabolomics, proteomics and bioinformatics.
 This proposal directly supports NIAID’s mission to understand and treat infectious diseases, particularly those
posing public health threats. Given schistosomiasis’ societal impacts, new drugs with distinct MOAs are urgently
needed. The proposed studies will establish a foundation for future R01-level research support and prepare me
to lead an independent research program for mechanism-driven drug discovery in infectious diseases.
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