Targeted Protein Degradation: The New Frontier of Antimicrobial Discovery?

Abstract

Targeted protein degradation aims to hijack endogenous protein quality control systems to achieve direct knockdown of protein targets. This exciting technology utilizes event-based pharmacology to produce therapeutic outcomes, a feature that distinguishes it from classical occupancy-based inhibitor agents. Early degrader candidates display resilience to mutations while possessing potent nanomolar activity and high target specificity. Paired with the rapid advancement of our knowledge in the factors driving targeted degradation, the expansion of this style of therapeutic agent to a range of disease indications is eagerly awaited. In particular, the area of antibiotic discovery is sorely lacking in novel approaches, with the Antimicrobial Resistance (AMR) crisis looming as the next potential global health calamity. Here, the current advances in targeted protein degradation are highlighted, and potential approaches for designing novel antimicrobial protein degraders are proposed, ranging from adaptations of current strategies to completely novel approaches to targeted protein degradation.

General and Robust Chemoenzymatic Method for Glycan-Mediated Site-Specific Labeling and Conjugation of Antibodies: Facile Synthesis of Homogeneous Antibody–Drug Conjugates

“…Taken together, the results suggest that ADCs made by this method carrying 6–8 payloads per antibody might result in an optimal potency and safety profile. In addition to ADCs, the azido-tagged antibodies described here can be also used for other antibody conjugations, such as site-selective construction of antibody–enzyme conjugates, , antibody–cell conjugates, , antibody–antibiotic conjugates, and lysosome-targeting chimeras for targeted protein degradation. − …”

Andrographolide Derivatives Target the KEAP1/NRF2 Axis and Possess Potent Anti‐SARS‐CoV‐2 Activity

“…As E3 ligase binders, andrographolide and its derivatives might also be utilized for targeted protein degradation, an emerging area in drug development. [52] Protein degraders are on the rise in developing novel therapies for the treatment of microbial and viral diseases,[ 53 , 54 ] and we assume that KEAP1 degradation could represent a promising strategy to combat SARS‐CoV‐2 infections.…”

Targeted Protein Degradation for Infectious Diseases: from Basic Biology to Drug Discovery

“…25 It has proven to cover different classes of protein targets, making it particularly attractive for extension into other diseases, including infectious diseases. 26,27 Remarkably, PROTAC technology has been successfully implemented for preclinical studies for viral diseases 28 and, more recently also for bacterial diseases (BacPROTACs). 29 This represents an exciting opportunity for expanding its scope to other pathogens, for a full exploitation in infectious diseases drug discovery.…”

“…Remarkably, PROTAC technology has been successfully implemented for preclinical studies for viral diseases and, more recently also for bacterial diseases (BacPROTACs) . This represents an exciting opportunity for expanding its scope to other pathogens, for a full exploitation in infectious diseases drug discovery. , Definitely, this approach needs further study to untap its great potential in relation to (i) the advantage of its catalytic MoA, (ii) the possibility to overcome drug resistance, (iii) the selection of anti-infective targets classified as “undruggable” by the classical occupancy-driven approach, (iv) the “recycling” of inhibitors coming from unsuccessful drug discovery programs, and (v) the chance for combination therapies.…”