DMREF: Accelerated discovery of metastable but persistent contact insecticide crystal polymorphs for enhanced activity and sustainability

New York University, New York NY

Investigators

Abstract

Non-technical Description: The World Health Organization estimates that malaria and other vector-borne infectious diseases, such as Zika or dengue fever, are responsible for more than 700,000 deaths worldwide annually. An essential component in the fight against malaria is the control of disease vectors through the use of contact insecticides for indoor residual spraying and insecticide-treated nets. Contact insecticides are powders of organic crystalline materials. As mosquitoes rest on the powder particles, they absorb the active substance through their tarsi (feet) to lethal effect. New York University investigators previously demonstrated that the efficacy of contact insecticides strongly depends on the identity of their crystalline forms, otherwise known as polymorphs, which have identical molecular compositions but different crystal structures. The more active polymorphs must also exhibit a high stability against transformation to less active polymorphs for the duration of their application. The central objective of this project is a knowledge-guided design, through computation and experiment, of metastable crystalline forms with superior properties for their target application. In the context of contact insecticides, this will allow less toxicant to be used, reduce environmental impact, and, thereby, meet key sustainability goals on multiple fronts. Various workshops, including Computer Crystals for Kids, Machine Learning for Kids, and Crystal Kaleidoscope, will convey the science of the project to K-12 students. Special attention will be provided to engage Black, Latino, and Native American students through the Collegiate Science Technology Entry Program. Technical Description: The application of metastable polymorphs of molecular crystals in the management of vector-borne diseases such as malaria and dengue fever through innovations in contact insecticide formulations represents a new and sustainable target of opportunity. Accelerated discovery of such metastable polymorphs with low thermodynamic yet high kinetic stability constitutes a key challenge that can only be met using a tightly integrated computational and experimental workflow. Starting with twelve known contact insecticides approved by the World Health Organization for indoor residual spraying (including pyrethroids, organophosphates, carbamates, and neonicotinoids), the project will explore innovative approaches to crystal polymorphs that meet the aforementioned criteria, which are essential to insecticide efficacy that relies on physical contact between insect tarsi and crystal surfaces in indoor residual spraying applications and insecticide-treated nets. Experimentally, these metastable polymorphs can be obtained from melt or solution, by (cross-)nucleation, phase transformations, or growth under nanoconfinement. The experimental work will be complemented by the development of a theoretical framework focused on the formation of energetically accessible polymorphs – driven by both thermodynamic and kinetic factors – as well as the transformation between different polymorphs and their surface properties. These tasks are beyond the reach of standard computational tools, requiring the development of new theoretical methodologies that combine the strength of enhanced molecular simulations and machine learning. Initial computational results will be validated by experimental data to improve the theoretical framework. Similarly, theoretical predictions will be used to guide and refine experimental protocols. This iterative loop of mutual feedback will eventually converge toward comprehensive and reliable workflows that will accelerate the discovery and development of metastable polymorphs with exceptional properties, in accord with the goals of the Materials Genome Initiative. Various workshops, including Computer Crystals for Kids, Machine Learning for Kids, and Crystal Kaleidoscope, will convey the science of the project to K-12 students. Special attention will be provided to engage Black, Latino, and Native American students through the Collegiate Science Technology Entry Program. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.