Targeted protein degradation (TPD), discovered twenty years ago through the PROTAC technology, is rapidly developing thanks to the implication of many scientists from industry and academia. PROTAC chimeras are heterobifunctional molecules able to link simultaneously a protein to be degraded and an E3 ubiquitin ligase. This allows the protein ubiquitination and its degradation by 26S proteasome. PROTACs have evolved from small peptide molecules to small non-peptide and orally available molecules. It was shown that PROTACs are capable to degrade proteins considered as "undruggable" i.e. devoid of well-defined pockets and deep grooves possibly occupied by small molecules. Among these "hard to drug" proteins, several can be degraded by PROTACs: scaffold proteins, BAF complex, transcription factors, Ras family proteins. Two PROTACs are clinically tested for breast (ARV471) and prostate (ARV110) cancers. The protein degradation by proteasome is also induced by other types of molecules: molecular glues, hydrophobic tagging (HyT), HaloPROTACs and homo-PROTACs. Other cellular constituents are eligible to induced degradation: RNA-PROTACs for RNA binding proteins and RIBOTACs for degradation of RNA itself (SARS-CoV-2 RNA). TPD has recently moved beyond the proteasome with LYTACs (lysosome targeting chimeras) and MADTACs (macroautophagy degradation targeting chimeras). Several techniques such as screening platforms together with mathematical modeling and computational design are now used to improve the discovery of new efficient PROTACs.

The establishment of latent infection in long-lived cells is the main obstacle to HIV cure or sustained remission without antiretroviral therapy. The most developed therapeutic strategies, in current clinical trials are mainly based on the concept of "shock and kill". They include latency reversing agents (LRAs) to re-activate HIV transcription that can be associated with immunomodulatory treatments. The objective is to eliminate virus-producing cells or to induce the control of HIV after anti-retroviral therapy cessation. HIV reservoir or cancer cells have a number of mechanisms in common. They can escape the immune system and persist by overexpressing survival molecules. This review presents a synthesis of current therapeutic approaches as well as the therapeutic perspectives related to the field of oncology.

Body size is an intrinsic property of living organisms that is intimately linked to the developmental program to produce fit individuals with proper proportions. Final size is the result of both genetic determinants and sophisticated mechanisms adapting size to available resources. Even though organs grow according to autonomous programs, some coordination mechanisms ensure that the different body parts adjust their growth with the rest of the body. In Drosophila, Dilp8, a hormone of the Insulin/Relaxin family is a key player in this inter-organs coordination and is required together with its receptor Lgr3 to limit developmental variability. Recently, the transcriptional co-activator Yki (homologue of YAP/TAZ factors in mammals) was shown to regulate dilp8 expression and contribute to the coordination of organ growth in Drosophila.

Alcohol use disorder is a devastating illness with a profound health impact, and its development is dependent on both genetic and environmental factors. This disease occurs over time and requires changes in brain gene expression. There is converging evidence suggesting that the epigenetic processes may play a role in the alcohol-induced gene regulations and behavior such as the intervention of DNA methylation and histone acetylation. Histone acetylation, like histone methylation, is a highly dynamic process regulated by two classes of enzymes: histone acetyltransferases and histone deacetylases (HDACs). To date, 18 human HDAC isoforms have been characterized, and based on their sequence homologies and cofactor dependencies, they have been phylogenetically categorized into 4 main classes: classes I, II (a and b), III, and IV. In the brain, expression of the different classes of HDACs varies between cell types and also in their subcellular localization (nucleus and/or cytosol). Furthermore, we recently showed that a single ethanol exposure inhibits HDAC activity and increases both H3 and H4 histone acetylation within the amygdala of rats. In the brain of alcoholic patients, ethanol has been shown to induce histone-related and DNA methylation epigenetic changes in several reward regions involved in reward processes such as hippocampus, prefrontal cortex, and amygdala. We recently demonstrated alteration of histone H3 acetylation levels in several brain regions from the reward circuit of rats made dependent to alcohol after chronic and intermittent exposure to ethanol vapor. In neuronal cell line culture, ethanol was shown to induce HDAC expression. In mouse and rat brain, numerous studies reported epigenetic alterations following ethanol exposure. We also demonstrated that both the expression of genes and the activity of enzymes involved in epigenetic mechanisms are changed after repeated administrations of ethanol in mice sensitized to the motor stimulant effect of ethanol (a model of drug-induced neuroplasticity). Numerous studies have shown that HDAC inhibitors are able to counter ethanol-induced behaviors and the ethanol-induced changes in the levels of HDAC and/or levels of acetylated HDAC. For example, trichostatin A (TSA) treatment caused the reversal of ethanol-induced tolerance, anxiety, and ethanol drinking by inhibiting HDAC activity, thereby increasing histone acetylation in the amygdala of rats. Another study demonstrated that TSA prevented the development of ethanol withdrawal induced anxiety in rats by rescuing deficits in histone acetylation induced by increased HDAC activity in the amygdala. We have demonstrated that treatment with the HDAC inhibitor sodium butyrate blocks both the development and the expression of ethanol-induced behavioral sensitization in mice. In this context, converging evidence indicates that HDAC inhibitors could be useful in counteracting ethanol-induced gene regulations via epigenetic mechanisms, that is, HDAC inhibitors could affect different acetylation sites and may also alter the expression of different genes that could in turn counteract the effect of ethanol. Recent work in rodents has shown that systemic administration of pan HDAC class I and II inhibitors, TSA and N-hydroxy-N-phenyl-octanediamide [SuberoylAnilide Hydroxamic Acid] (SAHA), and of the more selective inhibitor (mainly HDAC1 and HDAC9) MS-275, decrease binge-like alcohol drinking in mice. SAHA selectively reduced ethanol operant self-administration and seeking in rats. Our previous study revealed that MS-275 strongly decreased operant ethanol self-administration in alcohol-dependent rats when administered 30 minutes before the session at the second day of injection. We also demonstrated that intra-cerebro-ventricular infusion of MS-275 increases acetylation of Histone 4 within the nucleus accumbens and the dorsolateral striatum, associated to a decrease in ethanol self-administration by about 75%. MS-275 also diminished both the motivation to consume ethanol (25% decrease), relapse (by about 50%) and postponed reacquisition after abstinence. Both literature and several of our studies strongly support the potential therapeutic interest of targeting epigenetic mechanisms in excessive alcohol drinking and strengthen theinterest of focusing on specific isoforms of histone deacetylases.

The etiology of autism spectrum disorders (ASD) is believed to be multifactorial and to involve genetic and environmental components. Environmental chemical exposures are increasingly understood to be important in causing neurotoxicity in fetuses and newborns. Recent data from the Centers for Disease Control and Prevention in the United States suggest a substantial increase in ASD prevalence, only partly explicable by factors such as diagnostic substitution. Bisphenol A (BPA) is an ubiquitous xenoestrogen widely employed in a variety of consumer products including plastic and metal food and beverage containers, dental sealants and fillings, medical equipment and thermal receipts. Therefore, most people are exposed almost continuously to BPA in industrialized countries. Sources of BPA exposure are predominantly diet, but also through inhalation or dermal absorption. BPA can be measured in many human fluids and tissues including saliva, serum, urine, amniotic fluid, follicular fluid, placental tissue and breast milk. There is concern that BPA exposure may influence human brain development and may contribute to the increasing prevalence of neurodevelopmental and behavioural problems. Epigenetic mechanisms are suggested by a mouse study that demonstrated that BPA exposure during gestation had long lasting, transgenerational effects on social recognition. Previous epidemiological studies suggested a relationship between maternal BPA exposure and ASD. A recent study of 46 children with ASD and 52 controls found for the first time a direct association between children with ASD and BPA exposure and demonstrated that BPA is not metabolized well in children with ASD. The metabolomic analyses showed a correlation between ASD and essential amino acid metabolism pathways. Essential amino acids are precursors of neurotransmitters, for example tryptophan for serotonin. Fetal and prenatal BPA exposure was suggested to perturb the serotonergic system in rat and mice models. On the other hand, hyperserotonemia was reported in approximately one-third of autistic patients and also in relatives. Moreover, neuroimaging studies revealed two fundamentally different types of serotonin synthesis abnormality in children with autism compared to age-matched nonautistic children, a difference in whole-brain capacity and focal abnormalities. Finally, decreased serotonin transporter and serotonin receptor binding have been reported in both children and adults with autism. So, the link between BPA and autism could be a defect of the normal in utero or perinatal serotonergic system development. In France, BPA was banned in baby bottles in 2010 and in any food or beverage packaging since January 2015. Therefore, there is an urgent need to find safe alternatives in the use of BPA in the manufacture of industrial products.

Chromatin structure in eukaryotes and its modulation by epigenetic mechanisms enable the regulation of the different nuclear processes. Perturbation of epigenetic mechanisms can thus affect the proper functioning of cells, and numerous diseases have been linked to the deregulation of the activity of epigenetic effectors in human. The reversibility of epigenetic mechanisms has allowed the development of "Epigenetic drugs" or "Epidrugs". In a chemical biology approach, we have made use of the importance of eukaryotic epigenetic mechanisms to find drug leads that specifically affect pathogens responsible for neglected diseases. Our work on histone deacetylase 8 from Schistosoma mansoni (smHDAC8) has enabled us to design drug leads that show stronger selectivity for the pathogen enzyme than for its human homologs. Specifically, we have used a structure-based approach to understand the structural specificities of the smHDAC8 enzyme compared to the human enzymes, notably human HDAC8. The structure of smHDAC8 in complex with various pan-HDAC drugs led to the design of inhibitors that make use of all the structural specificities of this enzyme and that can be stabilized in the smHDAC8 catalytic pocket through a pathogen-specific clamp. Collectively, our results provide the proof of concept that epigenetic enzymes from pathogens can be targeted to develop anti-pathogenic epidrugs in the fight against neglected diseases. Our results also provide information that can be used to develop epidrugs to fight human diseases, including cancer.

Type I interferons play a central role in the establishment of an innate immune response against viral infections and tumor cells. Shortly after their discovery in 1957, several groups have looked for small molecules capable of inducing the expression of these cytokines with therapeutic applications in mind. A set of active compounds in mice were identified, but because of their relative inefficiency in humans for reasons not understood at the time, these studies fell into oblivion. In recent years, the characterization of pathogen recognition receptors and the signaling pathways they activate, together with the discovery of plasmacytoid dendritic cells, have revolutionized our understanding of innate immunity. These discoveries and the popularization of high-throughput screening technologies have renewed the interest for small molecules that can induce type I interferons. Proofs about their therapeutic potency in humans are expected very soon.

An imbalance of protein homeostasis caused by external or internal stress in the endoplasmic reticulum triggers the initiation of signalling pathways downstream of the IRE1, ATF6 and PERK sensors to a translational or transcriptional adaptive response known as UPR (Unfolded Protein Response). According to the intensity and duration of stress, the dual function of the UPR leads to either cell adaptation or cell death. UPR pathways in cancer cells are often altered and generally lead to an adaptation to an hostile environment. As the UPR becomes an emerging therapeutic target due to its increasing contribution to various diseases, we describe in this review various strategies that have been developed to discover new compounds enabling to manipulate the magnitude of ER stress in the context of cancer.

Since the early 1970's, investigators at Station Biologique de Roscoff (SBR), France, have been using marine organisms as models to describe molecular pathways conserved through evolution in mammalian cells (e.g. the cyclin-dependent kinases involved in the control of the cell division cycle). Some kinases are misregulated in various human pathologies, including cancers. Using a specialized screening approach, chemical libraries were analysed, using on-site facilities at Roscoff, in order to identify small chemical inhibitors of protein kinases. Eight chemical scaffolds produced by marine organisms were characterized as candidate drugs by our screening facility, some of which are being considered as chemical tools to pinpoint specific cellular functions of the targeted kinases. In this review, we describe our existing screening facilities and we discuss new perspectives related to marine bioprospecting.

Structural diversity oriented synthesis aims to fulfill the unoccupied tridimensional "chemical space" gap left by traditional chemical libraries. Through the development of novel synthetic strategies relying on divergent reactions, chemist is now able to realize in only two or three steps such library that ensures the access of a large number of products having a good quality in term of structural diversity. A few examples are presented to illustrate how this can be done in the context of increasing molecular complexity and diversity devoted to the discovery and optimization of bioactive compounds.