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Inhibiting Chikungunya Virus Protease using MTase-like Domain Interactions for Novel Antiviral Therapies.

Award Number: R01AI196176
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/23/2026
PERIOD OF PERFORMANCE END DATE: 01/31/2031

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Inhibiting Chikungunya Virus Protease using MTase-like Domain Interactions for Novel Antiviral Therapies. - Project Summary Chikungunya (CHIKV) is an RNA alphavirus that infects 3 million people in 45 countries including the US annually. Acute infection is flu-like, but in 40% of infections, debilitating joint pain emerges that can last for years. Infection during pregnancy also results in severe encephalopathy in newborns or aborted fetuses. Viral proteases are effective antiviral drug targets and are the standard of care for viral diseases (e.g HIV, hepatitis C, SARS-CoV- 2). The activity of the nsP2 protease from CHIKV (CHIKVP) is vital for infection. Inhibition of CHIKVP blocks processing of the viral polyprotein, prevents viral replication, lowers viral titers and stops disease progression. Thus, CHIKVP is an excellent antiviral drug target. To date, no effective antivirals of CHIKVP have been approved for acute or chronic infection. Our ultimate goal is to use insights into CHIKVP structure and dynamics to develop an inhibitor to oppose CHIKV infection, the resulting chronic pain and prevent pediatric neurological syndromes. CHIKVP is composed of a protease domain and a methyltransferase-like domain (MTL). To date, no functions of the MTL have been identified. In a search for novel CHIKVP binders, we identified ligands that bind to the MTL at an elongated cavity and allosterically inactivate the protease. The site shares structural homology with S-adenosyl methionine (SAM) cofactor binding sites, but does not bind SAM. The allosteric site binds to GTP, which suggests that a function such as RNA binding may be conserved in the MTL. Here we propose a research strategy for the development and direct comparison of CHIKVP active-site and allosteric inhibitors. We will build compounds derived from a large compound screen and also build from MTL-binding fragments we have already identified. We have developed NMR approaches that allow us to readily distinguish active-site from allosteric inhibitors. Importantly, we have developed approaches that allow us to monitor activity, binding and dynamics in solution without having to rely on freezing samples which is required for other structural techniques, to inform our inhibitor design. Recent data have suggested that RNA plays a critical role in CHIKVP function, enhancing protease activity. We have identified a site that we hypothesize binds RNA and describe a series of studies to understand the mechanism by which RNA impacts protease function. We will bring all these structural insights into our inhibitor development approach. At each step of development, we will closely monitor efficacy against viral infection for CHIKV and other related alphaviruses to determine whether pan-alphaviral inhibition is achievable with a given class of compounds. Critically, we will also implement a directed evolution approach across both domains of CHIKVP to predict the susceptibility of our inhibitors to resistance mutations. This will enable us to develop enduring antivirals and will also address longstanding unanswered questions about the favorability of allosteric inhibition in antiviral drug development.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $632,994 )
2026	2026	UNIVERSITY OF MASSACHUSETTS	101 COMMONWEALTH AVE	AMHERST	MA	01003	HAMPSHIRE	USA	Allergy and Infectious Diseases Research	000	1	2/23/2026	NEW	$632,994
														Subtotal = $632,994

Grand Total All Awards = $632,994

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Inhibiting Chikungunya Virus Protease using MTase-like Domain Interactions for Novel Antiviral Therapies.

Award Number: R01AI196176

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 02/23/2026

PERIOD OF PERFORMANCE END DATE: 01/31/2031

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