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

TL;DR

Researchers developed a new antiviral strategy that degrades the dengue virus capsid protein, showing effectiveness against resistant variants and multiple virus types.

Contribution

The study introduces a capsid degrader with differentiated pharmacology that overcomes resistance and targets nonstructural functions of the capsid.

Findings

RPG-01-132 degrades the DENV capsid via CRL4CRBN, disrupting infection pathways.

The degrader is effective against all four DENV serotypes and an ST148-resistant mutant.

Unlike ST148, RPG-01-132 affects nonstructural capsid functions, including interferon antagonism.

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 develop a DENV capsid degrader, RPG-01-132, that exhibits a broadened spectrum of activity against the four DENV serotypes and an ST148-resistant mutant 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 disrupts capsid-related pathways required for productive infection, including infectious virus output and capsid-mediated antagonism of the interferon response. This pharmacology is well-differentiated from ST148, which interferes with assembly of new virions, but has no demonstrated effect on the capsid’s nonstructural functions. These findings demonstrate that targeted protein degradation can thus enable antiviral pharmacology not observed with conventional antiviral inhibitors and that is resilient to point mutations that reduce inhibitor potency.

The authors demonstrate that targeted protein degradation of the dengue virus capsid suppresses infection through capsid-dependent pathways rather than classical inhibition, revealing a new antiviral strategy effective against resistant viral variants.

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