Targeted degrader technologies as prospective SARS-CoV-2 therapies

Abstract

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.

Keywords: PROTAC; SARS-CoV-2; antiviral; protease; targeted protein degradation.

FIGURE 1

Structure of SARS 3CLpro: (a) 3CLpro dimer with bound inhibitors (orange) in the active sites of the dimer (PDB ID:6XHM); (b) 3CLpro structure active site with subpocket nomenclature (single chain, rotated with respect to (a).

FIGURE 2

Small molecules that have been studied to treat SARS-CoV-2.

FIGURE 3

Solvent-accessible moieties of representative 3CLpro inhibitor chemotypes. Three-dimensional co-crystal structures of select 3CLpro inhibitor chemotypes and corresponding 2D structure representations indicating solvent-exposed heavy atoms (increased exposure indicated by darker blue highlights).

FIGURE 4

Illustration of a prospective ML300-based 3CLpro degrader. The design incorporates the CRBN E3 ligase recruiter pomalidomide linked to an ML300-derived warhead via a two-PEG amide linker.

FIGURE 5

Potential convergent retrosynthesis of ML300 derivative-based 3CLpro degraders.