Sunday, May 18, 2025
5/18/2025
Novel Structure-Based Therapeutic Discovery for Balamuthia mandrillaris - ABSTRACT Infections by Balamuthia mandrillaris cause granulomatous amoebic encephalitis (GAE) with a >92% fatality rate. Current treatments lack strong scientific support, leading to limited options and poor resolution of infections. Classified as a category B NIAID emerging infectious pathogen, B. mandrillaris faces obstacles in therapeutic development due to poor understanding of the pathophysiology, absence of validated targets, and low industrial interest. The project team combines expertise in amoeba biology from Dr. Christopher A. Rice at Purdue University, medicinal chemistry from Dr. Lori Ferrins, and molecular modeling from Dr. Mary Jo Ondrechen, both at Northeastern University. Previous research by this project team identified two compounds, Omipalisib and PKIS40, known human PI3K inhibitors, with activity better than currently recommended therapeutics against B. mandrillaris by the CDC. The project team has extensive experience re-optimizing human kinase inhibitors for parasitic diseases, and possess the complementary skills to position them to drive this program to success. Aim 1 is focused first on understanding the SAR and SPR. Using commercially available compound libraries we will enumerate compounds that can be made, and will prioritize compounds for synthesis using molecular docking (the Ondrechen lab has already built and evaluated a homology model). Compounds that demonstrate they can adopt a viable binding mode will be synthesized, and then evaluated for in vitro activity in Aim 2. This will occur simultaneously for both Omipalisib and PKIS40 chemotypes which were chosen because they are: 1) low micromolar inhibitors of B. mandrillaris which is better than the current chemotherapeutics; 2) there is a good selectivity index versus mammalian cells; and 3) there is a wealth of information in the literature that can be used to help inform optimization. Aim 2 will focus on the evaluation of all compounds synthesized in Aim 1 for their on-target activity against BmPI3K, and phenotypic evaluation against the trophozoites. At the conclusion of the project, the compounds that meet the Target Candidate Criteria, laid out in the proposal, will be prioritized for progression through secondary cysticidal and cytopathogenicity screening assays, pharmacokinetic, and a small in vivo proof-of- concept efficacy study with the top 2 lead candidates (although no funding is requested for this work). The development of new drug(s) would have a significant impact on the treatment of the orphan diseases caused by B. mandrillaris and this is the first-in-class project that seeks to optimize PI3K inhibitors for GAE using both phenotypic and target-based approaches. By the end of this project, we will have identified several compounds that are suitable to enter future secondary biological assays, and in vivo proof-of-concept studies against B. mandrillaris, and we will have chemically validated a novel target for this fatal disease.
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