Strategies for Tuning the Selectivity of Chemical Probes that Target Serine Hydrolases

Abstract

Serine hydrolases comprise a large family of enzymes that have diverse roles in key cellular processes, such as lipid metabolism, cell signaling, and regulation of post-translation modifications of proteins. They are also therapeutic targets for multiple human pathologies, including viral infection, diabetes, hypertension, and Alzheimer disease; however, few have well-defined substrates and biological functions. Activity-based probes (ABPs) have been used as effective tools to both profile activity and screen for selective inhibitors of serine hydrolases. One broad-spectrum ABP containing a fluorophosphonate electrophile has been used extensively to advance our understanding of diverse serine hydrolases. Due to the success of this single reagent, several robust chemistries have been developed to further diversify and tune the selectivity of ABPs used to target serine hydrolases. In this review, we highlight approaches to identify selective serine hydrolase ABPs and suggest new synthetic methodologies that could be applied to further advance probe development. ll

Lipolytic enzymes inhibitors: A new way for antibacterial drugs discovery

“…Based on these aforementioned results, and given the strong affinity of our OXs and CyCs for M. tb lipolytic enzymes, these inhibitors might target and impair the activity of various (Ser/Cys)-based enzymes involved in several processes of M. tb life cycle, thus resulting in bacterial death without any (or only very low) cytotoxicity towards host cells. Accordingly, target(s) identification experiments were next conducted by applying ABPP approach [27,33,34,[64][65][66][67] (Figure 5). Here, HPOX and CyC17, which selectively inhibit M. tb growth in culture broth medium only, were selected for such experiments [54,61].…”

A screen of covalent inhibitors in Mycobacterium tuberculosis identifies serine hydrolases involved in lipid metabolism as potential therapeutic targets

“…The copyright holder for this preprint (which this version posted June 8, 2021. ; https://doi.org/10.1101/2021.06.07.447460 doi: bioRxiv preprint 4 established successful strategies to optimize compound selectivity (Adibekian et al, 2011;Bachovchin et al, 2010;Chang et al, 2013;Faucher et al, 2020). Therefore, SHs are a highly diverse and 'druggable' family of targets whose function in bacteria remains poorly defined.…”

Fluorophosphonates on‐Demand: A General and Simplified Approach toward Fluorophosphonate Synthesis

“…Although a variety of reactive functional groups have been employed to covalently modify SHs, [1c,5] activated phosphonate warheads, including fluorophosphonates (FPs) [6] and p ‐nitrophenylphosphonates ( p NPs), [7] have been amongst the most utilized as ABPs (Figure 1A). Additionally, comparative analyses of activated phosphonates of differing chemotypes [8] highlight the benefits of having access to a toolbox of probes with readily tunable reactivity [8b,9] for labeling SHs. All these examples serve to highlight that structurally diverse probes are of immense value to better understand SH roles in various biological contexts.…”