Targeted degrader technologies as prospective SARS-CoV-2 therapies

•Continual evolution of SARS-CoV-2 warrants adaptive therapeutic approaches.•3CLpro is a well-characterized and important protein for viral replication.•3CLpro inhibitor co-crystal structures guide potential degrader development.•Degrader design requires synergy of computational and synthetic chemistry expertise.•Targeted protein degradation is the next frontier for antiviral therapies. COVID-19 remains a severe public health threat despite the WHO declaring an end to the public health emergency in May 2023. Continual development of SARS-CoV-2 variants with resistance to vaccine-induced or natural immunity necessitates constant vigilance as well as new vaccines and therapeutics. Targeted protein degradation (TPD) remains relatively untapped in antiviral drug discovery and holds the promise of attenuating viral resistance development. From a unique structural design perspective, this review covers antiviral degrader merits and challenges by highlighting key coronavirus protein targets and their co-crystal structures, specifically illustrating how TPD strategies can refine existing SARS-CoV-2 3CL protease inhibitors to potentially produce superior protease-degrading agents.