Univ. Lille, Inserm, Institut Pasteur de Lille, U1177, Drugs and Molecules for Living Systems, 3 rue du Pr Laguesse, 59000, Lille, France.
Published: September 2022
AI Article Synopsis
Article Abstract
Endoplasmic reticulum aminopeptidase 2 (ERAP2) is a key enzyme involved in the trimming of antigenic peptides presented by Major Histocompatibility Complex class I. It is a target of growing interest for the treatment of autoimmune diseases and in cancer immunotherapy. However, the discovery of potent and selective ERAP2 inhibitors is highly challenging. Herein, we have used kinetic target-guided synthesis (KTGS) to identify such inhibitors. Co-crystallization experiments revealed the binding mode of three different inhibitors with increasing potency and selectivity over related enzymes. Selected analogues engage ERAP2 in cells and inhibit antigen presentation in a cellular context. 4 d (BDM88951) displays favorable in vitro ADME properties and in vivo exposure. In summary, KTGS allowed the discovery of the first nanomolar and selective highly promising ERAP2 inhibitors that pave the way of the exploration of the biological roles of this enzyme and provide lead compounds for drug discovery efforts.
The research introduces a new method called "seleno-click" to create amide-linked inhibitors targeting the protein Mcl-1, building on a previous technique known as kinetic target-guided synthesis (KTGS).
This new seleno-click approach utilizes the high reactivity of selenocarboxylates to improve the reaction with electron-rich azides, broadening the potential applications of KTGS.
The effectiveness of this method is illustrated by producing a specific Mcl-1 inhibitor at both 37 °C and a lower temperature of 4 °C, indicating its usefulness for sensitive biological targets.
We showcase the successful combination of photochemistry and kinetic target-guided synthesis (KTGS) for rapidly pinpointing enzyme inhibitors. KTGS is a fragment-based drug discovery (FBDD) methodology in which the biological target (BT) orchestrates the construction of its own ligand from fragments featuring complementary reactive functionalities. Notably, fragments interacting with the protein binding sites leverage their spatial proximity, facilitating a preferential reaction.
Pathogenic free-living amoebae (pFLA) pose serious risks for central nervous system infections, making it crucial to find new chemical agents to fight these pathogens.
The study focuses on glucokinase (Glck), a metabolic enzyme with minimal similarity to human counterparts, as a promising target for developing inhibitors.
Using a novel "shotgun" multifragment kinetic target-guided synthesis (KTGS) strategy, researchers identified 12 effective inhibitors against three different pFLA glucokinase enzymes, showcasing KTGS's effectiveness even in the absence of detailed structural information.
Nucleic acids play crucial roles in transferring cellular information and gene regulations. DNA and RNA molecules have been associated with multiple human diseases and thus offer opportunities for exploring small molecule-based therapeutics. However, developing target-selective molecules possessing well-defined biological activity, has always been challenging.
Kinetic target-guided synthesis (KTGS) is a powerful screening approach that enables identification of small molecule modulators for biomolecules. While many KTGS variants have emerged, a majority of the examples suffer from limited throughput and a poor signal/noise ratio, hampering reliable hit detection. Herein, we present our optimized multifragment KTGS screening strategy that tackles these limitations.
