Development of novel antivirals for arthritogenic alphaviruses

About This Grant

Project summary: Development of Antivirals for Arthritogenic Alphaviruses This NIH grant proposal aims at the optimization of a New World (NW) alphavirus-specific quinazoline scaffold for the development of an anti-Old World (OW) arthritogenic alphavirus therapeutic candidate. With a particular focus on Chikungunya virus and other alphaviruses with a pandemic potential, this project responds to an urgent public health need for effective antiviral treatments for OW alphaviruses, given the recent increase in global prevalence of OW alphavirus infections. Dr. Chung's research group has made significant advancements in developing a quinazolinone-based antiviral specifically targeting NW alphaviruses like Venezuelan Equine Encephalitis Virus, exhibiting remarkable efficacy in preclinical models. This success, coupled with the compound's unique mechanism of action targeting the viral replicase complex, positions the quinazoline scaffold as a valid starting point for developing effective antivirals for other alphaviruses. However, the compound series necessitates significant enhancement in potency against OW alphaviruses. The team has identified a key residue that contributes to the NW alphavirus-specific antiviral spectrum. Here by elucidating the molecular interactions and clashes between the quinazolinone scaffold and OW alphavirus replicase complexes, the team aims to develop next- generation inhibitors with enhanced efficacy toward OW arthritogenic alphaviruses. Recognizing the need to enhance the potency of the quinazoline series against OW alphaviruses, the project proposes three Specific Aims undertaking a comprehensive and systemic approach integrating structural insights, medicinal chemistry, and preclinical evaluations. Dr. Luo's work in Specific Aim 1 focuses on mapping molecular interactions and clashes between the current quinazolinone scaffold and the OW alphavirus replicase complex, providing critical structural insights that will inform the design of new inhibitors in Specific Aim 2 led by Dr. Bannister. Specific Aim 2 efforts are directed towards identifying chemical groups leading to resistance in OW alphaviruses, designing and synthesizing new compounds tailored for OW alphaviruses, and ultimately developing lead candidates with optimized pharmacological profiles. Dr. Chung, in Specific Aim 3, will assess these novel antivirals in vitro and in vivo, supporting the structure-activity study for Aim2. Aim 3 will also study the mechanisms of action and resistance of the series. The overarching goal of the project is to deliver novel, potent therapeutic candidates for OW arthritogenic alphaviruses. With a highly integrated team of experts and a meticulous approach spanning molecular structural biology, medicinal chemistry, and virology, this project holds the promise of advancing preclinical development, ultimately addressing a critical gap in public health preparedness against OW alphavirus infections. Upon successful completion, the project will deliver promising therapeutic candidates ready for advanced preclinical development to address the critical needs for arthritogenic alphaviruses therapeutics.