Degraders of the dengue virus capsid protein exhibit differentiated pharmacology relative to capsid inhibitors

ABSTRACT: Due to the limited size of viral genomes, most viral proteins are multifunctional; yet most direct-acting antivirals are designed as single-function inhibitors. The dengue virus (DENV) capsid protein serves as a building block for new virions while also interacting with multiple host factors to remodel the cellular environment. Using established capsid inhibitor ST148 as a targeting ligand, we developed a DENV capsid degrader, RPG-01-132, that exhibits a broadened spectrum of activity against the four DENV serotypes and a known ST148-resistant virus. Using multiple approaches, we show that RPG-01-132's sub-micromolar antiviral activity is due to CRL4CRBN-dependent degradation of capsid and that this mechanism both prevents formation of virions and blocks capsid's antagonism of the interferon response. This pharmacology is well-differentiated from ST148, which prevents virion budding but has no demonstrated effect on capsid's nonstructural functions. Targeted protein degradation can thus enable improved activity spectrum and new antiviral pharmacology.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Eric Fischer  

LAB HEAD: Eric Fischer

PROVIDER: PXD063557 | Pride | 2026-03-30

REPOSITORIES: Pride