The AUTOTAC chemical biology platform for targeted protein degradation via the autophagy-lysosome system.

Targeted protein degradation allows targeting undruggable proteins for therapeutic applications as well as eliminating proteins of interest for research purposes. While several degraders that harness the proteasome or the lysosome have been developed, a technology that simultaneously degrades targets and accelerates cellular autophagic flux is still missing. In this study, we develop a general chemical tool and platform technology termed AUTOphagy-TArgeting Chimera (AUTOTAC), which employs bifunctional molecules composed of target-binding ligands linked to autophagy-targeting ligands. AUTOTACs bind the ZZ domain of the otherwise dormant autophagy receptor p62/Sequestosome-1/SQSTM1, which is activated into oligomeric bodies in complex with targets for their sequestration and degradation. We use AUTOTACs to degrade various oncoproteins and degradation-resistant aggregates in neurodegeneration at nanomolar DC50 values in vitro and in vivo. AUTOTAC provides a platform for selective proteolysis in basic research and drug development.

Vedolizumab-Induced De Novo Extraintestinal Manifestations.

Background: Vedolizumab is an α4ß7 integrin antagonist with gut-specific effects on lymphocyte and monocyte trafficking. Although the treatment is beneficial for inflammatory bowel disease (IBD), the effects of vedolizumab on extraintestinal manifestations (EIMs) have not been well described. The gut-specific effects of the medication may have diverse outcomes on EIMs. We hypothesize that EIMs may be unmasked by systemic availability of gut-homing effector cells. Aim: The goal of this study is to describe de novo EIMs of IBD patients who were started on vedolizumab. Methods: A retrospective chart review of 71 patients from January 2011 to October 2017, including clinical and medication history and colonoscopy results, was performed. Results: EIMs occurred in 26.7% of patients who were started on vedolizumab. The most common EIMs were arthralgias, perianal fistula, and pyoderma gangrenosum. There was a trend toward a greater occurrence of EIMs in patients with Crohn's disease compared to ulcerative colitis. Conclusion: Our retrospective study suggests that inhibition of gut-specific effector cells results in activated lymphocytes and/or monocytes that cause inflammation in other tissues. More studies are needed to confirm these observations and to develop biomarkers that predict patients at risk for EIMs and perianal fistulas while on vedolizumab.