VCTR: New Insecticides for malaria control: Discovery research for the identification of new chemical entities for malaria control

This project completed in December 2015.

New Insecticides for Malaria Control: Discovery Research for the Identification of New Chemical Entities for Malaria Control was a continuation of research initiated under the FNIH’s Vector-based Control of Transmission: Discovery Research (VCTR) program. VCTR was itself an extension of the Bill & Melinda Gates Foundation’s Grand Challenges in Global Health initiative. As a subset of activities under the VCTR program, the New Insecticides for Malaria Control program addressed the urgent need for new chemicals to kill mosquitoes that transmit malaria. Current efforts rely heavily on the use of available insecticides for use on bednets, for indoor residual spraying and for application of chemical larvicides. Available insecticides are limited in number and the only one class of compound (pyrethroids) can safely be used on bednets. The situation is grim as mosquitoes have evolved resistance to the compounds currently in use. This program sought to address the situation by supporting research projects to identify new active ingredients with novel modes of action to safely and effectively kill mosquitoes including those resistant to existing insecticides.

In 2010, the FNIH released a request for proposals soliciting discovery research projects to identify new chemical entities with novel modes of action to be the basis for the further development of insecticides with mosquitocidal properties. Following a rigorous scientific and programmatic review process including peer review by an external committee of experts, four awards were funded. The four projects sought to characterize molecular targets in Anopheles mosquitoes that are essential for mosquito survival and to develop small molecule inhibitors of those targets as leads for insecticide development. The four projects that were pursued with support from VCTR were:

  • Molecular mosquitocides: Development of an innovative and robust, platform-based approach for sustainable insecticidal control of Anopheline mosquitoes.
  • Voltage-Sensitive Potassium Channel as a New Target for Mosquitocides.
  • Development of synthetic chemical mimics of selectively insecticidal natural peptides.
  • High throughput discovery of chemical that inhibit kidney failure in the malaria vector anopheles gambiae.

Goals

  • Identify and characterize novel structures, pathways and enzymes in Anopheles mosquitoes as a starting point, i.e. targets, for discovery of new insecticides for malaria control.
  • Validate those targets using molecular genetic and chemical methods.
  • Identify small molecule inhibitors of targets with properties predictive of insecticidal properties.

Results & Accomplishments

A number of Anopheles mosquito enzymes and transporters were identified and characterized as potential targets for new insecticidal compounds with novel modes of action.

Scientific Publications

Biodistribution and trafficking of hydrogel nanoparticles in adult mosquitoes. Paquette CC, Phanse Y, Perry JL, Sanchez-Vargas I, Airs PM, Dunphy BM, Xu J, Carlson JO, Luft JC, DeSimone JM, Bartholomay LC, Beaty BJ. PLoS Negl Trop Dis. 2015 May 21;9(5):e0003745. doi: 10.1371/journal.pntd.0003745.

Mosquitocidal carbamates with low toxicity to agricultural pests: an advantageous property for insecticide resistance management. Swale DR, Carlier PR, Hartsel JA, Ma M, Bloomquist JR. Pest. Manag. Sci. 2014 doi: 10.1002/ps.3899

Voltage-Sensitive Potassium Kv2 Channels as New Targets for Insecticides. Bloomquist JR, Mutunga JR, Islam RM, Verma R, Ma R, Totrov MM, Carlier, PR. 2015 ACS Symposium Series 1172, pp. 71-81.

In silico screening for compounds that match the pharmacophore of omega-hexatoxin-Hv1a leads to discovery and optimization of a novel class of insecticides.Tedford HW, Steinbaugh BA, Bao L, Tait BD, Tempczyk-Russell A, Smith W, Benzon GL, Finkenbinder CA, Kennedy, RM. Pesticide Biochemistry and Physiology,2013 DOI:10.1016/j.pestbp.2013.01.009 Volume 106, Issue 3, July 2013, Pages 124–140.

Pharmacological Validation of an Inward-Rectifier Potassium (Kir) Channel as an Insecticide Target in the Yellow Fever Mosquito Aedes aegypti. Rouhier, M. F., Raphemot, R., Denton, J. S., & Piermarini, P. M. PLoS ONE 2014 9(6), e100700. doi:10.1371/journal.pone.0100700.

Malpighian tubules as novel targets for mosquito control. Piermarini P.M., Esquivel C.J., Denton J.S. International Journal of Environmental Research and Public Health 2017 Volume 14, Issue 2, February.

Partners

Private-Sector Partners:
Bill & Melinda Gates Foundation*
Vestaron Corporation

Academic Partners:
Colorado State University
Ohio State University
University of Florida

*Provided financial or in-kind support for this program.

FNIH Contact

Stephanie James, Ph.D., Senior Vice President of Science; sjames@fnih.org