Proteolysis Targeting Chimera (PROTACs): An Attractive Technology in CVD Therapeutics—Opportunities and Challenges

Cardiovascular diseases (CVDs) affect the heart and blood vessels. Stroke and heart attack are the leading cause of death globally, responsible for 17.9 million annual deaths. Both these conditions need prompt management, surgical intervention, and drug therapy thereafter. Other CVDs also require chronic therapy. Most of the currently available drugs are small molecules, which face issues like drug resistance, side effects, and reduced activity against many proteins. PROTAC technology, which utilizes ATP-dependent ubiquitin-proteasome system (UPS) pathway to degrade the protein of interest, can be a prospective solution. PROTAC is a bifunctional molecule containing a ligand for engaging E3 ligase, a linker, and another ligand to connect to the target protein for degradation. E3 ligase labels the protein with ubiquitin, which then undergoes degradation. Several proteins like IRAK4, TRIM 24, and ion channel proteins are involved in the pathogenesis of CVDs. PROTAC technology can not only target the dysfunctional proteins but also overcome the resistance to drugs like statins which on prolonged use cause protein overexpression. However, it faces disadvantages including low bioavailability and cell specificity. Another pressing issue is the availability and synthesis of specific PROTACs for research. To cater to this need, several service providers offer support to drug discovery teams for PROTAC design and synthesis. Translation of this technology to clinical trials has begun for cancer, however, for CVDs no suitable candidate has been developed. This chapter mainly focuses on the development of PROTACs for the treatment of various CVDs, their advantages, limitations, and future scope in clinical practice.