Targeted protein degraders may act as promising antivirals

Viruses are prone to mutations that make them resistant to existing drugs. Drugs that directly target a virus typically work as inhibitors, binding to a viral protein to hinder its function. So if that virus mutates and causes a change to the protein, the inhibitor may not bind as tightly, potentially making the antiviral less effective.

Stanford University chemical biologist Priscilla Li-ning Yang is interested in an approach where tight binding isn’t the be-all and end-all. She’s exploring the use of targeted protein degraders, which are small molecules that help eliminate proteins. On Sunday at ACS Fall 2023, she presented proof-of-concept work in cell culture models showing that several degraders demonstrated better antiviral properties than some known inhibitors.

Targeted protein degraders work by binding both the target protein and an E3 ligase enzyme; the E3 ligase, brought close to the target protein, labels it for destruction. The degrader only needs to bind tightly enough to enable that interaction with the E3 ligase, and, afterwards, it detaches to bind to another target protein.

“You don’t even necessarily want super tight binding,” Yang said. “Because you have the potential to iteratively degrade multiple copies of the target protein.” That can be useful because resistance often occurs from a single mutation that reduces binding, she said.

Yang’s talk presented unpublished work in which her group created two degraders to target a viral envelope protein. An envelope protein, on the surface of a virion, is required both for the virus to enter into the cell and for it to make new particles, she said. To create a suitable degrader, Yang’s team started with experimental inhibitors of the dengue virus envelope protein, and added ligands that recruit an E3 ligase.

Tested head-to-head against the inhibitor they were based on, the degraders demonstrated greater antiviral potency against dengue virus. The degraders were also still effective when tested against mutated proteins known to make the inhibitors less effective. Additionally, the degraders showed better broad-spectrum activity than the inhibitors against some other viruses in the same genus.

“The original compounds were really active against dengue virus. And they had modest activity, but not great activity, against West Nile virus, Japanese encephalitis virus, other mosquito borne flaviviruses,” Yang said. “When we converted them to being degraders, we saw much improved potency against all of the viruses.”

Yang also presented data from when her team tested an inhibitor-turned-degrader against hepatitis C virus, detailed in a 2019 paper (Nature Communications, DOI: 10.1038/s41467-019-11429-w). That degrader showed better activity against mutants that have resistance to the parental inhibitor, but was not more potent than the inhibitor, Yang said. The inhibitor—a peptide that’s approved by the US Food and Drug Administration—is already pretty large, and making it larger in the conversion to a degrader may have reduced its ability to penetrate the cell, she said.

The degrader approach may be subject to several limitations. For instance, the degraders are bigger than the inhibitors, which may make them harder to deliver, Yang said. She also noted it’s likely there are some protein targets that won’t be susceptible, because the virus will replete them too quickly. She’s interested in exploring which targets are worth attacking, and testing the technique in animal models.

Many researchers are already studying targeted protein degradation, but much of the work so far has been concentrated on treating cancer. But targeted protein degradation (TPD) “holds great promise beyond oncology,” said George Burslem, who studies chemical biology at the University of Pennsylvania and was not involved with the research, via email.

“There have been several forays into the development of antivirals by TPD previously,” Burslem said, “but I think it’s largely been neglected since it’s such a new technology and because of the lack of suitable ligands for conversion into degraders.”