A Perspective on Newly Emerging Proteolysis-Targeting Strategies in Antimicrobial Drug Discovery

Abstract

Targeted protein degradation is a new aspect in the field of drug discovery. Traditionally, developing an antibiotic includes tedious and expensive processes, such as drug screening, lead optimization, and formulation. Proteolysis-targeting chimeras (PROTACs) are new-generation drugs that use the proteolytic mechanism to selectively degrade and eliminate proteins involved in human diseases. The application of PROTACs is explored immensely in the field of cancer, and various PROTACs are in clinical trials. Thus, researchers have a profound interest in pursuing PROTAC technology as a new weapon to fight pathogenic viruses and bacteria. This review highlights the importance of antimicrobial PROTACs and other similar “PROTAC-like” techniques to degrade pathogenic target proteins (i.e., viral/bacterial proteins). These techniques can perform specific protein degradation of the pathogenic protein to avoid resistance caused by mutations or abnormal expression of the pathogenic protein. PROTAC-based antimicrobial therapeutics have the advantage of high specificity and the ability to degrade “undruggable” proteins, such as nonenzymatic and structural proteins.

An Update Review of Approaches to Multiple Action-Based Antibacterials

“…There is much scope for selective protein destruction strategies mediated by bacterial PROTACS (BacProtacs) as discussed in a recent review of the area by Venkatesan et al [71] and a preview by Burslem [72], in which relatively small heterobifunctional molecules are highlighted as promising BacPROTACS. Morreale et al [73] have developed the BacProtac technology with small molecules and this approach should be very useful in informing the development of powerful new antibiotics or of combinations with different antibacterial effects.…”

PROTACs: A novel strategy for cancer drug discovery and development

“…At the present, more than 10 PROTAC degraders have entered clinical Phase I‐II trials with ARV‐471 and ARV‐110 from Arvinas, Inc as the most advanced ones for the treatment of recurrent breast cancer and prostate cancer, respectively 46–49 . However, PROTAC still faces many challenges 50–65 . A typical PROTAC degrader consists of three components: the target‐binding small molecule ligand (protein of interest, POI), the E3 ligase ligand and the appropriate linker that connects the two components (Figure 1).…”

“… 46 , 47 , 48 , 49 However, PROTAC still faces many challenges. 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 A typical PROTAC degrader consists of three components: the target‐binding small molecule ligand (protein of interest, POI), the E3 ligase ligand and the appropriate linker that connects the two components (Figure 1 ). 50 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 E3 ligases and the corresponding ligands are important as the driving force of protein degradation.…”

Development of a GC-376 Based Peptidomimetic PROTAC as a Degrader of 3-Chymotrypsin-like Protease of SARS-CoV-2

“…Proteolysis targeting chimera (PROTAC) technology provides an attractive approach to modulate protein levels of therapeutic target by hijacking the cellular machinery responsible for the physiological elimination of endogenous proteins. − This strategy has been widely established to be successful in targeting cancer-related proteins, with more than a dozen drug candidates entering clinical investigation. − On the contrary, the applicability of PROTAC technology in the field of antivirals remains marginal. − Only a few studies of PROTAC molecules targeting viral proteins have been reported in the case of hepatitis and influenza viruses, − and just a preliminary attempt investigating the applicability of PROTAC technology against coronaviruses (CoV) has been documented . The latter study targets the viral spike protein receptor binding domain of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).…”