A team, led by Professors Lan Ke, Zhou Haibing, and Associate Professor Wu Shuwen from Wuhan University has unveiled a novel broad-spectrum antiviral degrader, with their findings published in Journal of Medicinal Chemistry.

Their research, Identification of Novel Amino Acid-based PROTACs Exhibiting Broad-spectrum Antiviral Activity Against Enteroviruses, introduces an innovative application of amino acid-mediated targeted protein degradation (AATacs) technology, developing a potent degrader targeting the 3D polymerase of enteroviruses (3Dpol).

This approach simulates the body's natural "N-end rule" degradation pathway, using small amino acids as "degradation signals" to guide the cell's endogenous degradation system in targeting and eliminating viral core proteins.

The interdisciplinary research approach circumvents the limitations of traditional drug development and provides a highly promising new strategy for achieving efficient, low-toxicity broad-spectrum antiviral therapy.

Using acylthiourea as a scaffold and the principles of AATacs, the team developed a series of novel compounds and identified N-6 as the optimal candidate.

Mechanistic studies confirmed that N-6 possesses high target selectivity, inducing degradation of viral 3D polymerase and activating the host cell's "ubiquitin-proteasome" and "autophagy-lysosome" degradation pathways.

In antiviral activity tests, N-6 demonstrated broad-spectrum potential, proving effective against EV-A71 and other pathogenic enteroviruses, including CV-A16, CV-A21, CV-B1, and EV-D68.