National Institutes of Health funds development of resistance-breaking insecticides to reduce malaria transmission
April 13, 2009
Researchers from Virginia Tech and Molsoft LLC have received a five-year, $3.557 million grant from the National Institute of Allergy and Infectious Diseases (NIAID) to continue their promising work on a new class of resistance-breaking insecticides to reduce malaria transmission.
At present, the first line of defense against the malaria mosquito in sub-Saharan African is insecticide treated nets (ITNs). However, growing resistance to the pyrethroid insecticides used on the nets threatens to render this protection ineffective. The research team led by Paul Carlier, professor of chemistry in the College of Science at Virginia Tech, is striving to develop a new class of insecticides that will be safe for use on nets and effective against pyrethroid-resistant mosquitoes.
The NIAID award builds on results from three years (2005-08) of research funded by the Foundation for the National Institutes of Health (FNIH) through the Grand Challenges in Global Health initiative of the Bill and Melinda Gates Foundation. This earlier project was led by Jeffrey R. Bloomquist, professor of toxicology and pharmacology in the entomology department of Virginia Tech's College of Agriculture and Life Sciences.
"In 2005, we had a great multidisciplinary team and a promising new idea," said Carlier.
The team combined chemists, entomologists, and biologists in the United States with malaria mosquito control experts in Kenya. The focus was to develop insecticides that strongly interfere with acetylcholinesterase (AChE), a key enzyme in the mosquito brain, while leaving the related human enzyme untouched. The promising new idea was that the malaria mosquito, Anopheles gambiae, would pick up two inactive molecules from a bed net that would then bind to AChE within the mosquito and thus disable it. "That initial concept has not yet been realized," said Carlier.
However, the team made two important advances which form the basis for the NIAID grant for "Development of vector-specific, resistance breaking insecticides to reduce malaria transmission."
"First, we discovered we could modify the chemical structures of existing AChE-targeting insecticides in a way that should significantly lower their toxicity to mammals," said Carlier. Since these compounds still retain significant insecticidal activity against the malaria mosquito, they could prove ideal for deployment on ITNs. Two patent applications have been filed and commercial interest has been expressed in the potentially safer compounds, he said.
"Second, we figured out how to inhibit target site-resistant mosquito AChE and demonstrated this effect in vitro," said Carlier. "The challenge now is to modify these inhibitors so that they can make their way into the mosquito's brain and thus exert the desired insecticidal action."
The new insecticides should also be less likely to cause the emergence of new target site-resistant strains, he said. And the team has developed a number of other strategies to ward against metabolic resistance mechanisms in the Anopheles gambiae mosquito.
In addition to principal investigator Carlier and co-investigator Bloomquist, other co-investigators on the NIAID-funded research team are Jianyong Li, associate professor of biochemistry in the College of Agriculture and Life Sciences at Virginia Tech, and Maxim Totrov, principal scientist at Molsoft LLC of La Jolla, Calif.
Carlier is responsible for the design of synthetic routes to the AChE-based insecticides. Bloomquist is responsible for the pharmacological and toxicological assessment of the proposed insecticides. Li, who has extensive experience in isolating and crystallizing a number of important mosquito enzymes in native form, is responsible for expressing, purifying, and crystallizing various Anopheles gambiae acetylcholinesterases. Totrov, an expert in rational computer-aided drug design methods and in the biophysics of protein-ligand interactions, has worked with Carlier and Bloomquist on the FNIH award since 2006.
Carlier, Bloomquist, and Li are members of the Vector-Borne Disease Research Group at Virginia Tech, whose mission is to elucidate the fundamental mechanisms involved in the transmission and pathogenesis of vector-borne infectious organisms, deepen the understanding of the nature of infectious disease, and lead the search for novel approaches to disease mitigation.
Carlier received his undergraduate degree from Hamilton College in 1983 and his Ph.D. from Massachusetts Institute of Technology in 1988.