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“Development of VHL-recruiting STING PROTACs that suppress innate immunity” has been published online in Cellular and Molecular Life Sciences. The first author is Dr. Zhichuan Zhu in the Pengda Liu lab.

Zhichuan Zhu
Zhichuan Zhu PhD, first author

This is a collaboration with the School of Pharmacy,  Dr. Lindsey James, and Dr. Blossom Damania of Microbiology and Immunology, driven by a collaborative effort from postdoc Zhichuan Zhu PhD in the Liu lab and graduate student Rebecca Johnson from the James lab of the School of Pharmacy. Members are also associated with Linebereger Comprehensive Cancer Center.

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Activation of the STING signaling is pivotal for host defense against viral/bacterial infection and creating immune environment for tumor rejection, while STING hyperactivation causes autoimmune diseases. Thus, efforts from both acamedia and industry have been devoted in developing small molecules to properly modulate STING activity that can be used in treating various diseases. PROTAC (proteolysis targeting chimera) is composed of two chemical modules linking the protein of interest to a given E3 ligase, which results in efficient ubiquitination and degradation of the target protein. Here, from a joint effort from Liu and James Lab at UNC, we develop and validate a PROTAC that degrades STING protein in kidney cancer cells in a time- and dose-effective manner. This STING-PROTAC is screened from a series of candidates with rational designs, and it consists of a STING agonist and a VHL (E3 ligase) recruiting warhead directing STING to proteosome for destruction. We also unexpectedly find that endogenous VHL E3 ligase serves as a bona fide E3 ligase earmarking STING for ubiquitination and degradation. Our developed STING-PROTAC can further speed up this process by recognizing distinct regions on STING. Cells treated with STING-PROTAC have reduced STING protein levels, accompanied by reduced interferon production and are easier to die after virus infection. In summary, we design the first-class VHL-recruiting STING PROTAC and demonstrate an interesting example of hijacking a physiological E3 ligase by PROTAC to enhance target protein degradation.