Themed collection Covalent Drug Discovery

19 items
Editorial

Introduction to the themed collection on Covalent Drug Discovery

Guest editors Keriann Backus, Zhengying Pan and Lyn Jones introduce the themed collection on Covalent Drug Discovery.

Graphical abstract: Introduction to the themed collection on Covalent Drug Discovery
From the themed collection: Covalent Drug Discovery
Opinion

Covalent drugs targeting histidine – an unexploited opportunity?

Targeted covalent modulation of histidine in ligand binding sites will expand the druggable proteome.

Graphical abstract: Covalent drugs targeting histidine – an unexploited opportunity?
From the themed collection: Covalent Drug Discovery
Opinion

A primer on harnessing non-enzymatic post-translational modifications for drug design

Our primer discusses the current issues faced when medicinal chemists try to leverage highly reactive electrophiles for drug development.

Graphical abstract: A primer on harnessing non-enzymatic post-translational modifications for drug design
From the themed collection: Covalent Drug Discovery
Opinion

Covalent PROTACs: the best of both worlds?

Covalent PROTACs combine the cutting edge research areas of targeted covalent inhibitors (TCIs) and proteolysis targeting chimeras (PROTACs).

Graphical abstract: Covalent PROTACs: the best of both worlds?
From the themed collection: Covalent Drug Discovery
Review Article

Recent applications of covalent chemistries in protein–protein interaction inhibitors

Often, large molecules are required to effectively disrupt protein–protein interactions (PPIs). Exploiting covalent chemistries may realize potent therapeutics boasting more “drug-like” properties with longer residence times.

Graphical abstract: Recent applications of covalent chemistries in protein–protein interaction inhibitors
From the themed collection: Covalent Drug Discovery
Review Article

Reactivity-based chemical-genetic study of protein kinases

In this review, we describe the development and application of chemical-genetic strategies that feature the use of covalent inhibitors targeting cysteine residues to dissect the cellular functions of individual protein kinases.

Graphical abstract: Reactivity-based chemical-genetic study of protein kinases
From the themed collection: Covalent Drug Discovery
Review Article

Covalent cannabinoid receptor ligands – structural insight and selectivity challenges

X-ray crystallography and cryogenic electronic microscopy have provided significant advancement in the knowledge of GPCR structure and have allowed the rational design of covalent GPCR ligands.

Graphical abstract: Covalent cannabinoid receptor ligands – structural insight and selectivity challenges
From the themed collection: Covalent Drug Discovery
Review Article

β-Lactam antibiotic targets and resistance mechanisms: from covalent inhibitors to substrates

Overview of β-lactam antibiotics and the proteins with which they covalently interact, focusing on penicillin-binding proteins and serine β-lactamases.

Graphical abstract: β-Lactam antibiotic targets and resistance mechanisms: from covalent inhibitors to substrates
From the themed collection: Covalent Drug Discovery
Review Article

Recent advances in the development of covalent inhibitors

This is the short review focusing on recent advances of covalent warheads that can be applied to the development of potential covalent inhibitors.

Graphical abstract: Recent advances in the development of covalent inhibitors
From the themed collection: Covalent Drug Discovery
Research Article

Integrating a covalent probe with ubiquicidin fragment enables effective bacterial infection imaging

A covalent probe attached to the UBI antimicrobial peptide enhances membrane binding retention time through iminoboronate formation, thus improving bacterial infection imaging in vivo.

Graphical abstract: Integrating a covalent probe with ubiquicidin fragment enables effective bacterial infection imaging
From the themed collection: Covalent Drug Discovery
Research Article

Development of subtype-selective covalent ligands for the adenosine A2B receptor by tuning the reactive group

Selectivity of covalent ligands for the adenosine A2B receptor was induced by tuning the reactivity and orientation of the warhead.

Graphical abstract: Development of subtype-selective covalent ligands for the adenosine A2B receptor by tuning the reactive group
From the themed collection: Covalent Drug Discovery
Research Article

Structure–activity relationships of hydrophobic alkyl acrylamides as tissue transglutaminase inhibitors

Our investigation of small, irreversible TG2 inhibitors identifies key components that confer enhanced efficiency, and reveals potential discrepancies in the use of current crystallographic models for predicting inhibitor potency.

Graphical abstract: Structure–activity relationships of hydrophobic alkyl acrylamides as tissue transglutaminase inhibitors
From the themed collection: Covalent Drug Discovery
Open Access Research Article

Identification of the first structurally validated covalent ligands of the small GTPase RAB27A

A novel Rab27A construct enables elucidation of covalent ligand binding, paving the way for structure-guided approaches against this challenging target.

Graphical abstract: Identification of the first structurally validated covalent ligands of the small GTPase RAB27A
From the themed collection: Covalent Drug Discovery
Research Article

Covalent sortase A inhibitor ML346 prevents Staphylococcus aureus infection of Galleria mellonella

Covalent sortase A inhibitor ML346 prevents Galleria mellonella from Staphylococcus aureus infection by interfering in the transpeptidation activity of sortase A for anchoring surface proteins into staphylococci envelope.

Graphical abstract: Covalent sortase A inhibitor ML346 prevents Staphylococcus aureus infection of Galleria mellonella
From the themed collection: Covalent Drug Discovery
Research Article

Profiling MAP kinase cysteines for targeted covalent inhibitor design

The knowledge of reactive cysteine locations is valuable for targeted covalent inhibitor design. Here we used an advanced molecular simulation tool to assess and rationalize the cysteine reactivities for all 14 MAP kinases.

Graphical abstract: Profiling MAP kinase cysteines for targeted covalent inhibitor design
From the themed collection: Covalent Drug Discovery
Open Access Research Article

Activity-based protein profiling reveals deubiquitinase and aldehyde dehydrogenase targets of a cyanopyrrolidine probe

We report the characterization of a UCHL1 covalent inhibitor based on a thiazole cyanopyrrolidine scaffold and a closely-related activity-based probe (ABP) which was used to generate a quantitative profile for on- and off-targets in human cells.

Graphical abstract: Activity-based protein profiling reveals deubiquitinase and aldehyde dehydrogenase targets of a cyanopyrrolidine probe
From the themed collection: Covalent Drug Discovery
Research Article

Peptidomimetic nitrile warheads as SARS-CoV-2 3CL protease inhibitors

This article describes peptidomimetic SARS-CoV-2 3CLpro inhibitors with a nitrile warhead with in vitro antiviral inhibition. Superior selectivity was observed for the nitrile warhead compared to the aldehyde against 3 human cathepsins (B, S and L).

Graphical abstract: Peptidomimetic nitrile warheads as SARS-CoV-2 3CL protease inhibitors
From the themed collection: Covalent Drug Discovery
Research Article

Deglycase-activity oriented screening to identify DJ-1 inhibitors

Tracking the esterase activity of DJ-1 via a fluorescent-based scalable assay to uncover and develop candidates with enhanced potency.

Graphical abstract: Deglycase-activity oriented screening to identify DJ-1 inhibitors
From the themed collection: Covalent Drug Discovery
Research Article

Irreversible inhibition of BoNT/A protease: proximity-driven reactivity contingent upon a bifunctional approach

A proximity-driven covalent bond with intrinsically less reactive warheads has been made possible by using a metal-chelating anchor for directed targeted covalent modification of Cys165 within the BoNT/A protease.

Graphical abstract: Irreversible inhibition of BoNT/A protease: proximity-driven reactivity contingent upon a bifunctional approach
From the themed collection: Covalent Drug Discovery
19 items

About this collection

This themed collection, guest edited by Dr Lyn Jones (Dana-Farber Cancer Institute), Professor Keriann Backus (UCLA) and Professor Zhengying Pan (Peking University), highlights the latest medicinal chemistry advances in covalent drug discovery. This collection will cover all aspects of covalent drug discovery, from the design of covalent drugs (including warheads, chemical probes and natural products) to their biological activity.
New articles will be added to the collection upon publication. Please return to this page frequently to see the collection grow.

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