Principal investigators Kylene Kehn-Hall, professor of virology in the Department of Biomedical Sciences and Pathobiology, and Mikell Paige and Dmitri Klimov of George Mason University (GMU) have been awarded a four-year R01 grant from the National Institutes of Health's National Institute of Allergy and Infectious Diseases (NIAID) to develop potential molecular treatments for the Venezuelan equine encephalitis virus.

TITLE
Developing capsid-importin alpha inhibitors for the treatment of VEEV infection

FUNDING AGENCY
NIAID; GMU; Virginia Tech (VT) is a subcontract.

TOTAL AWARD
Direct (GMU and VT):  $2,216,617
Indirect (GMU and VT): $633,429
Direct (VT): $658,861
Indirect (VT): $381,476

DURATION OF AWARD
Sept. 15, 2020 — Aug. 31, 2024

KEY FACULTY PERSONNEL
PI/PD: Mikell Paige (GMU), Dmitri Klimov (GMU), Kylene Kehn-Hall (VT)

SIGNFICANCE
Venezuelan equine encephalitis virus (VEEV) infects humans and is considered a public threat due to its easy dissemination and weaponization potential. In humans, it causes encephalitis, with severe cases resulting in death. Individuals who survive infection can still suffer from inflammation, behavioral changes, intellectual disability, and convulsions. No therapeutic treatment against VEEV currently exists. To address this threat, a novel pipeline will be developed, which creates and optimizes small molecule inhibitors of interactions between VEEV capsid, and human host protein importin alpha. The interaction of VEEV capsid with importin alpha prevents the innate immune system from fighting off the infection. This inhibitor developmental pipeline involves high-end biomolecular simulations coupled with in vitro and in vivo experiments synergistically testing and verifying in silico data. The proposed design pipeline is expected to produce more potent inhibitors capable of blocking the ability of VEEV to cause severe disease. The pipeline implements a rational design approach to molecular inhibitors and is generally applicable to other viral infections.