Rebecca Deprez-Poulain

Université de Lille · Faculty of Pharmaceutical Sciences and biology

A novel series of potent agonists of the bile acid receptor TGR5 bearing a dihydropyridone scaffold was developed from a high-throughput screen. Starting from a micromolar hit compound, we implemented an extensive structure-activity-relationship (SAR) study with the synthesis and biological evaluation of 83 analogues. The project culminated with th...

Metallo-β-lactamases (MBLs) contribute to the resistance of Gram-negative bacteria to carbapenems, last-resort antibiotics at hospital, and MBL inhibitors are urgently needed to preserve these important antibacterial drugs. Here, we describe a series of 1,2,4-triazole-3-thione-based inhibitors displaying an α-amino acid substituent, which amine was...

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 challe...

Kinetic target-guided synthesis and optimisation led to the first nanomolar ERAP2 inhibitors with outstanding selectivity. The binding modes of the most potent inhibitors were elucidated by X-ray crystallography. Our frontrunners engage target in cells and display good in vitro and in vivo pharmacokinetic properties. Abstract Endoplasmic reticulum...

Insulin-degrading enzyme (IDE) is a multifunctional protease due to the variety of its substrates, its various cellular locations, its conservation between species and its many non-proteolytic functions. Numerous studies have successfully demonstrated its implication in two main therapeutic areas: metabolic and neuronal diseases. In recent years, s...

Insulin degrading enzyme (IDE) is a zinc metalloprotease that cleaves numerous substrates among which amyloid-β and insulin. It has been linked through genetic studies to the risk of type-2 diabetes (T2D) or Alzheimer's disease (AD). Pharmacological activation of IDE is an attractive therapeutic strategy in AD. While IDE inhibition gave paradoxal a...

Chemical biology and drug discovery are two scientific activities that pursue different goals but complement each other. The former is an interventional science that aims at understanding living systems through the modulation of its molecular components with compounds designed for this purpose. The latter is the art of designing drug candidates, i....

An efficient one-pot procedure combining bromide conversion into azide followed by NiAAC for the preparation of 1,5-disubstituted 1,2,3-triazoles has been developed. This procedure prevents the use of isolated azides, which are insufficiently commercially available and could be potentially unstable and difficult to handle. Moreover, this one-pot me...

Endoplasmic reticulum aminopeptidase 2, ERAP2, is an emerging pharmacological target in cancer immunotherapy and control of autoinflammatory diseases, as it is involved in antigen processing. It has been linked to the risk of the development of spondyloarthritis, and it associates with the immune infiltration of tumours and strongly predicts the ov...

In the last 5 years, cellular thermal shift assay (CETSA), a technology based on ligand-induced changes in protein thermal stability, has been increasingly used in drug discovery to address the fundamental question of whether drug candidates engage their intended target in a biologically relevant setting. To analyze lysates from cells submitted to...

Target-guided synthesis has emerged as an elegant and efficient lead- and drug-discovery strategy. [...]

Kinetic target-guided synthesis (KTGS) is an original discovery strategy allowing a target to catalyze the irreversible synthesis of its own ligands from a pool of reagents. Though pioneered almost two decades ago, it only recently proved its usefulness in medicinal chemistry, as exemplified by the increasing number of protein targets used, the wid...

1,2,3-triazole is a well-known scaffold that is. [...]

Although several ADAMs (A disintegrin-like and metalloproteases) have been shown to contribute to the amy-loid precursor protein (APP) metabolism, the full spectrum of metalloproteases involved in this metabolism remains to be established. Transcriptomic analyses centred on metalloprotease genes unraveled a 50% decrease in ADAM30 expression that in...

Insulin-degrading enzyme, IDE, is a metalloprotease implicated in the metabolism of key peptides such as insulin, glucagon, β-amyloid peptide. Recent studies have pointed out its broader role in the cell physiology. In order to identify new drug-like inhibitors of IDE with optimal pharmacokinetic properties to probe its multiple roles, we ran a hig...

Insulin degrading enzyme (IDE) plays key roles in degrading peptides vital in type 2 diabetes, Alzheimer's, inflammation, and other human diseases. However, the process through which IDE recognizes peptides that tend to form amyloid fibrils remained unsolved. We used cryoEM to understand both the apo- and insulin-bound dimeric IDE states, revealing...

CryoEM data collection and processing statistic

CryoEM map and model refinement statistics

Data collection and structure refinement statistics

Distances and angles between center of mass of different domains of IDE cryoEM and crystal structures.

Hydroxamic acids are outstanding zinc chelating groups that can be used to design potent and selective metalloenzyme inhibitors in various therapeutic areas. Some hydroxamic acids display a high plasma clearance resulting in poor in vivo activity, though they may be very potent compounds in vitro. We designed a 57-member library of hydroxamic acids...

Background: On-pump cardiac surgery provokes a predictable perioperative myocardial ischaemia-reperfusion injury which is associated with poor clinical outcomes. We determined the occurrence of time-of-the-day variation in perioperative myocardial injury in patients undergoing aortic valve replacement and its molecular mechanisms. Methods: We st...

Endoplasmic reticulum aminopeptidase 2 assists with the generation of antigenic peptides for presentation onto Major Histocompatibility Class I molecules in humans. Recent evidence has suggested that the activity of ERAP2 may contribute to the generation of autoimmunity, thus making ERAP2 a possible pharmacological target for the regulation of adap...

Enhanced expression of the aggrecanase ADAMTS5 (A Disintegrin And Metalloproteinase with Thrombospondin type 1 motifs; member 5) has been observed in adipose tissue (AT) of obese rodents. Here, we have investigated the role of ADAMTS5 in adipogenesis, AT expansion and associated angiogenesis. In vitro differentiation of precursor cells into mature...

Supplementary material.

Transcriptomic data.

Although several ADAMs (A disintegrin-like and metalloproteases) have been shown to contribute to the amyloid precursor protein (APP) metabolism, the full spectrum of metalloproteases involved in this metabolism remains to be established. Transcriptomic analyses centred on metalloprotease genes unraveled a 50% decrease in ADAM30 expression that inv...

For the last 15 years, kinetic target-guided syntheses, including in situ click chemistry, have been used as alternative methods to find ligands to therapeutically relevant proteins. In this review, a comprehensive survey of biological targets used in kinetic target-guided synthesis covers historical and recent examples. The chemical reactions empl...

Insulin-degrading enzyme (IDE) is a protease that cleaves insulin and other bioactive peptides such as amyloid-β. Knockout and genetic studies have linked IDE to Alzheimer's disease and type-2 diabetes. As the major insulin-degrading protease, IDE is a candidate drug target in diabetes. Here we have used kinetic target-guided synthesis to design th...

Insulin degrading enzyme (IDE) is a zinc metalloprotease that degrades small amyloid peptides such as amyloid-â and insulin. So far the dearth of IDE-specific pharmacological inhibitors impacts the understanding of its role in the physiopathology of Alzheimer's disease, amyloid-â clearance, and its validation as a potential therapeutic target. Hit...

Over the last decade, there has been a large effort to target aggrecanases, which are responsible for the degradation of the aggrecan in the extracellular matrix of joints, in order to hopefully lead to new treatments for osteoarthritis. Only a few inhibitors have been effective in explants or rodent models and thus only a few have reached the clin...

Insulin degrading enzyme (IDE) is a highly conserved zinc metalloprotease that is involved in the clearance of various physiologically peptides like amyloid-beta and insulin. This enzyme has been involved in the physiopathology of diabetes and Alzheimer's disease. We describe here a series of small molecules discovered by screening. Co-crystallizat...

Osteoarthritis is a disabling disease characterized by the articular cartilage breakdown. Aggrecanases are potential therapeutic targets for the treatment of this pathology. At the starting point of this project, an acylthiosemicarbazide was discovered to inhibit aggrecanase-2. The acylthiosemicarbazide Zn binding group is also a convenient linker...

The APP metabolism has been extensively studied and likely deciphered in a large proportion. However, the characterization of new actors of the APP metabolism might help for a more subtle understanding of this APP metabolism and trafficking.We focused on the ADAMs and related proteins with the hypothesis that ADAMs and related proteins, under- or o...

We report efficient miniaturized conditions to prepare arrays of bicyclic lactams for screening. The nature of the solvent is usually an important factor of reactivity. At a small synthesis scale, when automated pipetting devices are required, physical properties of the solvent, such as surface tension and vapor pressure also become very important....

Malaria is severe infectious disease that causes between 655,000 and 1.2 million deaths annually. To overcome the resistance to current drugs, new biological targets are needed for drug development. Aminopeptidase M1 (PfAM1), a zinc metalloprotease, has been proposed as a new drug target to fight malaria. Herein, we disclosed the structure-activity...

Conditions are developed for the multicomponent reaction, which represent an efficient alternative to microwave procedures.

A diverse library of carboxylic acids was synthesized on solid-support. The screening on hNEP identified a low molecular weight hit. Structure–activity relationships around the hit highlighted the critical role of configuration for both chiral centers. The path, that involves a side reaction, to the potent and selective NEP optimised inhibitor is p...

An environment-friendly high-yielding method for the racemic and asymmetric diastereoselective preparation of indole alkaloids via Pictet–Spengler reaction is reported. The reaction proceeds with short reaction times under solvent-free and microwave-irradiation conditions.

A Passerini three component condensation between a carboxylic acid, an aldehyde, and an isocyanide at high temperature under solvent-free conditions was developed. This methodology allows the formation of a broad range of α-acyloxyamides in excellent yields in short reaction times.

Ullmann-type reactions are becoming a major tool in medicinal chemistry. In this article, we describe the use of these Copper-catalyzed reactions with various precursors, acyl-heteroarylamines or pyrazoles of interest for pharmacomodulation. To the medicinal chemist they offer new, usually untapped disconnection approaches to compounds of interest....

The protocol gives stereoselective access to Meyer′s chiral lactams in high yields and short times.

In this Letter we describe the design, synthesis, screening, and optimization of a new family of ADAMTS-5 inhibitors. These inhibitors display an original 1,2,4-triazole-3-thiol scaffold as a putative zinc binding-group. In vitro results are rationalized by in silico docking of the compounds in ADAMTS-5's crystal structure.

Five- and six-membered lactams were synthesized via a 4-center 3-component Ugi reaction by combining amines, isocyanides, and ketoacids under solvent-free microwave conditions. The reaction was carried out in much shorter times and the yields were improved in comparison to classical conditions.

Microwave solvent-free conditions developed for Meyers’ lactamization, a typical bielectrophile-binucleophile reaction that produces quaternary centers in a stereoselective manner, give access to Meyers’ chiral lactams in good yield and high diastereoselectivity in short times.

A two-step sequence involving an Ugi four-component reaction was developed for the preparation of 4-aminopiperidine-4-carboxylic acid derivatives. This strategy has led to the successful preparation of two drugs carfentanil and remifentanil in shorter times and better yields than previously described methods.

Aggrecanase-2, also called ADAMTS-5 (A Disintegrin and Metalloproteinase with ThromboSpondin motifs) is a metalloenzyme that degrades components of the extracellular matrix, and in particular the glycoprotein aggrecan, present in cartilage joints.1 In that context, inhibitors of this enzyme could result in efficient treatments for osteoarthritis. O...

Hydroxamates are valuable tools for chemical biology as well as interesting leads for medicinal chemistry. Although many hydroxamates display nanomolar activities against metalloproteases, only three hydroxamates have reached the market, among which is the HDAC inhibitor vorinostat. Failures in development are generally attributed to lack of select...

The side effects associated with tuberculosis therapy bring with them the risk of noncompliance and subsequent drug resistance. Increasing the therapeutic index of antituberculosis drugs should thus improve treatment effectiveness. Several antituberculosis compounds require in situ metabolic activation to become inhibitory. Various thiocarbamide-co...

Jointly organized by the French Société de Chimie Thérapeutique (SCT), the Royal Society of Chemistry (RSC, UK), the Société Royale de Chimie (SRC, Belgium) and the Koninklijke Vlaamse Chemische Vereniging (KVCV, Belgium), the 43 rd International conference on medicinal chemistry (RICT43) took place on July 2007 at the School of Pharmacy in Lille (...

In our ongoing research program aiming at the discovery of potent inhibitors for medicinally relevant of zinc-metalloproteases, we are very interested in identifying modulators of Insulin Degrading Enzyme (IDE, insulysin). We describe here the biological screening of this enzyme and the identification of hits, inhibiting IDE with IC50 in the microm...

Metalloproteases are a class of proteins involved in diverse and important biological phenomena such as cell proliferation, signalisation, multiplication and migration, hormonal signalisation, angiogenesis, pathogen growth. Numerous inhibitors of this enzyme class are described and some are important therapeutic classes: ACE or NEP inhibitors. This...

Insulysin or Insulin Degrading Enzyme (IDE) is a ubiquitous Zinc metalloprotease implicated in the clearance of numerous physiological peptides. Insulysin hydrolyses in particular beta-amyloid peptide and insulin, respectively implicated in Alzheimer disease and Diabetes. Also, it cleaves several peptides such as the insulin-like growth factor 2 (I...

Aggrecanase-2, also called ADAMTS-5 (A Disintegrin and Metalloproteinase with ThromboSpondin motifs) is a metalloenzyme that degrades components of the extracellular matrix, and in particular the glycoprotein aggrecan, present in cartilage joints. In that context, inhibitors of this enzyme could result in efficient treatments for osteoarthritis. On...

Les protéases exprimées dans le cycle erythrocytaire de Plasmodium falciparum sont des cibles thérapeutiques potentielles dans le traitement du paludisme. Nous avons découvert des inhibiteurs puissants de la PfAM1, une métallo-aminopeptidase du parasite. Ces composés présentent une activité sur l’enzyme parasitaire 1000 fois supérieure à celle sur...

We have successfully obtained 1,2,4-oxadiazol-5-one bioisoteres of Am580 or Tazarotene-like retinoids. In particular compound 4 displays an EC(50) of 26nM on RAR-beta.

We report here the parallel synthesis of 200 compounds based on squaric acid template. These compounds are obtained via a one-step solution-phase procedure starting from three squaric acid N-hydroxylamide esters precursors. The set of diverse reagents qualified (amines, anilines, amino-alcohols and amino-esters) makes this strategy suitable for the...

In this article, we compare drugs of natural origin to synthetic compounds and analyze the reasons why natural compounds occupy a place of choice in the current pharmacopoeia. The observations reported here support the design of synthetic compounds inspired from plant alkaloids and their biosynthetic pathway. Our reasoning leads to very efficient s...

Many natural privileged scaffolds contain a basic nitrogen atom, which often is a key element of pharmacophore and a chemically reactive centre as well. In our ongoing research program devoted to the design of targeted libraries based on acidic templates, we developed methods to convert privileged basic compounds -like natural alkaloids or drugs in...

Biphenyltetrazoles are recognized privileged structures. Among them, the therapeutically important class of sartans displays antagonistic activity on ATI receptors. We have developed a method for anchoring tetrazole derivatives via the heterocycle on a hydroxylated resin using zinc triflate. New Suzuki-Miyaura cross-coupling conditions are develope...

Hydroxamates are valuable tools for chemical biology as well as valuable leads for medicinal chemistry. Nevertheless pharmacokinetics and toxicity problems are encountered with these chemical series. These challenges have forced medicinal chemists to search for surrogates for this highly efficient ZBG. Recently, the first hydroxamate in 25 years ha...

We report here the convenient synthesis of 4H-1,2,4-triazole-3-thiols using di-2-pyridyl-thionocarbonate as the thiocarbonyl transfer reagent. This method is suitable for microplate parallel synthesis and produces samples in screening-ready condition. It uses two large sets of building-blocks: amines and hydrazides.

Proteases that are expressed during the erythocytic stage of Plasmodium falciparum are newly explored drug targets for the treatment of malaria. We report here the discovery of potent inhibitors of PfA-M1, a metallo-aminopeptidase of the parasite. These compounds are based on a malonic hydroxamic template and present a very good selectivity toward...