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

Abstract

Targeted protein degradation (TPD) is emerging as one of the most innovative strategies to tackle infectious diseases. Particularly, proteolysis-targeting chimera (PROTAC)-mediated protein degradation may offer several benefits over classical anti-infective small-molecule drugs. Because of their peculiar and catalytic mechanism of action, antiinfective PROTACs might be advantageous in terms of efficacy, toxicity, and selectivity. Importantly, PROTACs may also overcome the emergence of antimicrobial resistance. Furthermore, anti-infective PROTACs might have the potential to (i) modulate "undruggable" targets, (ii) "recycle" inhibitors from classical drug discovery approaches, and (iii) open new scenarios for combination therapies. Here, we try to address these points by discussing selected case studies of antiviral PROTACs and the first-in-class antibacterial PROTACs. Finally, we discuss how the field of PROTAC-mediated TPD might be exploited in parasitic diseases. Since no antiparasitic PROTAC has been reported yet, we also describe the parasite proteasome system. While in its infancy and with many challenges ahead, we hope that PROTAC-mediated protein degradation for infectious diseases may lead to the development of next-generation anti-infective drugs.

Proximity-Based Modalities for Biology and Medicine

“…, neurodegenerative diseases and infective diseases. Overcoming the blood–brain barrier and co-opting other organismal ubiquitin-proteasome systems , are major hurdles for developing PROTACs against neurodegenerative disease targets and anti-infective diseases targets, respectively.…”

“…, neurodegenerative diseases and infective diseases. Overcoming the blood–brain barrier and co-opting other organismal ubiquitin-proteasome systems , are major hurdles for developing PROTACs against neurodegenerative disease targets and anti-infective diseases targets, respectively. How to fast expand the E3 ligase landscape and the E3 ligand toolbox. Cereblon is so far the most prevalent E3 ligase for the first wave of PROTACs in clinical trials.…”

“…How to degrade untackled disease-causing proteins such as transcription factors and expand to disease areas beyond cancer and inflammatory diseases, e.g., neurodegenerative diseases and infective diseases. Overcoming the blood−brain barrier and co-opting other organismal ubiquitin-proteasome systems67,68 are major hurdles for developing PROTACs against neurodegenerative disease targets and anti-infective diseases targets, respectively. 2.…”

Discovery of First-in-Class PROTAC Degraders of SARS-CoV-2 Main Protease

“…These distinctive features position PROTAC as a potential game-changing technology in drug discovery that has been widely explored for degrading various disease-causing proteins. Harnessing these advantages, antiviral PROTACs via targeted protein degradation has been considered as a promising strategy for developing next-generation antiviral drugs to combat infectious diseases. − The antiviral PROTACs would improve resistance profiles to those of traditional inhibitors. , In our ongoing pursuit of COVID-19 drug discovery targeting M Pro , we present the design, synthesis, and evaluation of the first series of small-molecule PROTAC degraders targeting SARS-CoV-2 M Pro . Our work has led to the identification of MPD2 as a potent degrader of M Pro with a DC 50 value of 296 nM, demonstrating promising antiviral activity against various SARS-CoV-2 strains and exhibiting enhanced potency against nirmatrelvir-resistant viruses.…”

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).…”