Could PROTACs Protect Us From COVID-19?

PROTAC targeted protein degraders: the past is prologue

“…A large PPI study in SARS-CoV-2-infected cells revealed several potential druggable pathways and proteins that may be exploited by repurposing inhibitors 199 , and that could potentially be addressed by SARS-CoV-2-targeting PROTAC molecules. One provocative paper raised the possibility of targeting the viral envelope protein 200 , but SARS-CoV-2 catalytic virulence factors, such as its two proteases, Mpro and PLpro 201 , and the RNA-dependent RNA polymerase (Rdrp), which is the target of remdesivir 202 , are potentially targetable by a PROTAC. Importantly, Pfizer initiated a phase I trial of its orally bioavailable SARS-CoV-2 Mpro inhibitor, PF-07321332 (NCT04756531) in healthy individuals in February 2021, followed by a phase II/III study, in which the first patient was dosed in September 2021 (NCT04960202).…”

Non-small molecule PROTACs (NSM-PROTACs): Protein degradation kaleidoscope

“…For antiviral therapy, the innate advantages of PROTACs are overcoming drug resistance and removal of all protein function. Additional studies have shown that antiviral PROTACs stimulate the host immune response to virus 20 . In addition to the X-protein peptide PROTAC mentioned above, Wispelaere and his colleagues 174 adopted small molecule PROTACs to demonstrate the great potential of PROTACs in the antiviral field.…”

“…Furthermore, the overall PROTACs can artificially hijack the ubiquitin–proteasome system by forming a stable ternary complex with E3 ubiquitin ligase and POI, and then make the POI undergo sufficient ubiquitination and degradation by the proteasome 16 , 17 , 18 , 19 . Different from traditional small molecules, the POI degradation profile of PROTACs is dependent on the proximity-induced interactions between the E3 ubiquitin ligase and POI 20 , 21 . Therefore, researchers call the mode of action of PROTACs “event-driven” 22 , 23 .…”

Resources and computational strategies to advance small molecule SARS-CoV-2 discovery: Lessons from the pandemic and preparing for future health crises

“…In modern days, many different in silico approaches can be used to assist the design of a drug candidate or drug, from data (e.g., text and image) mining (e.g., annotated drug databases, antiviral peptide databases, electronic health patient records…), genome analysis, comparative genomics, multiple sequence alignments, visualization tools for epidemiological studies, analysis of macromolecular interaction networks, structural predictions (e.g., comparative modeling, protein folding…), antibody-drug conjugate, analysis of point mutations, protein docking, various types of molecular simulation engines (e.g., for proteins, peptides, small molecules, cell membrane, DNA, RNA, glycans, and interactions among these molecules…), binding pocket predictions, PROTACs (e.g., degradation of viral protein capsids), transcriptomic profile analysis, virtual screening (from small collections of approved drugs as in drug repositioning or repurposing projects to the screening of ultra-large virtual libraries), hit to lead optimization, drug combination, computational polypharmacology and compound profiling, ADMET prediction, multiparameter optimization methods associated with novel data visualization approaches, systems biology, systems pharmacology, with or without the use of machine learning and artificial intelligence (AI) algorithms depending on the type of methods, available data and the stage of the projects [19] , [77] , [80] , [127] , [128] , [129] , [130] , [131] , [132] , [133] , [134] , [135] , [136] , [137] , [138] , [139] , [140] , [141] , [142] , [143] , [144] , [145] , [146] , [147] , [148] , [149] , [150] , [151] , [152] , [153] , [154] , [155] , [156] , [157] , [158] , [159] , [160] , [161] , [162] , [163] , [164] , [165] , [166] , [167] , [168] , [169] , …”

“…Many different strategies can be used to identify disease prevention drugs and/or treatments. In the present context, considering the virus life cycle, one may aim at drugs acting at different stages of the infection (e.g., entry, replication, and dissemination…) [7] , [18] , [19] , [20] , [21] , [22] , [23] , [24] . The drugs could be small chemical compounds and (stapled) peptides [21] , [25] , [26] , [27] , [28] , [29] , [30] , [31] , [32] , therapeutic proteins including antibodies or nanobodies [33] , [34] , [35] , [36] , [37] , [38] , [39] , [40] , [41] , [42] , [43] , [44] , [45] , vaccines [46] , [47] and cells [48] , [49] , [50] .…”