Auswahl der wissenschaftlichen Literatur zum Thema „Pleiotropic prodrugs“

Of all the drugs launched on the market over the past decade, a substantial number of approved prodrugs have been significant, underscoring the importance of this prodrug to drug design. It is reported that 10% of all marketed drugs globally can be classified as prodrugs. The core goal of the prodrug strategy is to improve the undesirable properties of the drug molecule, including but not limited to insufficient solubility, low selectivity, poor chemical stability, poor taste, strong local irritation, significant pain, and possible systemic toxicity during metabolism in vivo. This review article includes the discussion of the phosphate prodrugs, ketone prodrugs, ester prodrugs, amide prodrugs, pH-responsive prodrugs, enzyme-activated prodrugs, carbamate prodrugs, liposomal prodrugs, and pleiotropic prodrugs. The latest research on prodrugs in the field of cancer, nano and antibacterial in recent years are also discussed. Through the research and application of the above chemical modification methods and the clinical application of prodrug technology in the fields of cancer treatment, nanotechnology, antimicrobial drugs, etc., researchers can design safer and more effective treatments to meet clinical needs and optimize the treatment experience of patients. At the same time, these studies not only confirm the importance of prodrug design in drug development, but also provide new ideas and methods for future drug design.

Alzheimer’s disease (AD) is a multifactorial neurodegenerative disease which is still poorly understood. The drugs currently used against AD, mainly acetylcholinesterase inhibitors (AChEI), are considered clinically insufficient and are responsible for deleterious side effects. AChE is, however, currently receiving renewed interest through the discovery of a chaperone role played in the pathogenesis of AD. But AChE could also serve as an activating protein for pleiotropic prodrugs. Indeed, inhibiting central AChE with brain-penetrating designed carbamates which are able to covalently bind to the enzyme and to concomitantly liberate active metabolites in the brain could constitute a clinically more efficient approach which, additionally, is less likely to cause peripheral side effects. We aim in this article to pave the road of this new avenue with an in vitro and in vivo study of pleiotropic prodrugs targeting both the 5-HT4 receptor and AChE, in order to display a neuroprotective activity associated with a sustained restoration of the cholinergic neurotransmission and without the usual peripheral side effects associated with classic AChEI. This plural activity could bring to AD patients effective, relatively safe, symptomatic and disease-modifying therapeutic benefits.

The role of phytochemicals as potential prodrugs or therapeutic substances against tumors has come in the spotlight in the very recent years, thanks to the huge mass of encouraging and promising results of the in vitro activity of many phenolic compounds from plant raw extracts against many cancer cell lines. Little but important evidence can be retrieved from the clinical and nutritional scientific literature, where flavonoids are investigated as major pro-apoptotic and anti-metastatic compounds. However, the actual role of these compounds in cancer is still far to be fully elucidated. Many of these phytochemicals act in a pleiotropic and poorly specific manner, but, more importantly, they are able to tune the reactive oxygen species (ROS) signaling to activate a survival or a pro-autophagic and pro-apoptosis mechanism, depending on the oxidative stress-responsive endowment of the targeted cell. This review will try to focus on this issue.

Cortistatin is a cyclic neuropeptide that recently emerged as an attractive therapeutic factor for treating inflammatory, autoimmune, fibrotic, and pain disorders. Despite of its efficiency and apparent safety in experimental preclinical models, its short half-life in body fluids and its potential pleiotropic effects, due to its promiscuity for several receptors expressed in various cells and tissues, represent two major drawbacks for the clinical translation of cortistatin-based therapies. Therefore, the design of new strategies focused on increasing the stability, bioavailability, and target specificity of cortistatin are lately demanded by the industry. Here, we generated by molecular engineering a new cortistatin-based prodrug formulation that includes, beside the bioactive cortistatin, a molecular-shield provided by the latency-associated protein of the transforming growth factor-β1 and a cleavage site specifically recognized by metalloproteinases, which are abundant in inflammatory/fibrotic foci. Using different models of sepsis, inflammatory bowel disease, scleroderma, and pulmonary fibrosis, we demonstrated that this latent form of cortistatin was a highly effective protection against these severe disorders. Noteworthy, from a therapeutic point of view, is that latent cortistatin seems to require significantly lower doses and fewer administrations than naive cortistatin to reach the same efficacy. Finally, the metalloproteinase-cleavage site was essential for the latent molecule to exert its therapeutic action. In summary, latent cortistatin emerges as a promising innovative therapeutic tool for treating chronic diseases of different etiologies with difficult clinical solutions and as a starting point for a rational development of prodrugs based on the use of bioactive peptides.

AbstractThe 5-nitroimidazole drug metronidazole has remained the drug of choice in the treatment of anaerobic infections, parasitic as well as bacterial, ever since its development in 1959. In contrast to most other antimicrobials, it has a pleiotropic mode of action and reacts with a large number of molecules. Importantly, metronidazole, which is strictly speaking a prodrug, needs to be reduced at its nitro group in order to become toxic. Reduction of metronidazole, however, only takes place under very low concentrations of oxygen, explaining why metronidazole is exclusively toxic to microaerophilic and anaerobic microorganisms. In general, resistance rates amongst the pathogens treated with metronidazole have remained low until the present day. Nevertheless, metronidazole resistance does occur, and for the treatment of some pathogens, especiallyHelicobacter pylori, metronidazole has become almost useless in some parts of the world. This review will give an account on the current status of research on metronidazole's mode of action, metronidazole resistance in eukaryotes and prokaryotes, and on other 5-nitroimidazoles in use.

Thiamine (vitamin B1) is essential for the brain. This is attributed to the coenzyme role of thiamine diphosphate (ThDP) in glucose and energy metabolism. The synthetic thiamine prodrug, the thioester benfotiamine (BFT), has been extensively studied and has beneficial effects both in rodent models of neurodegeneration and in human clinical studies. BFT has no known adverse effects and improves cognitive outcomes in patients with mild Alzheimer’s disease. In cell culture and animal models, BFT has antioxidant and anti-inflammatory properties that seem to be mediated by a mechanism independent of the coenzyme function of ThDP. Recent in vitro studies show that another thiamine thioester, O,S-dibenzoylthiamine (DBT), is even more efficient than BFT, especially with respect to its anti-inflammatory potency, and is effective at lower concentrations. Thiamine thioesters have pleiotropic properties linked to an increase in circulating thiamine concentrations and possibly in hitherto unidentified open thiazole ring derivatives. The identification of the active neuroprotective metabolites and the clarification of their mechanism of action open extremely promising perspectives in the field of neurodegenerative, neurodevelopmental, and psychiatric conditions. The present review aims to summarize existing data on the neuroprotective effects of thiamine thioesters and give a comprehensive account.

Abstract Immune checkpoint inhibition (ICI) has established immunotherapy as the first line of treatment in a subset of cancers. However, there are still many patients and cancer types where ICI is not effective, representing a significant unmet clinical need for novel immunotherapies to expand the clinical options for patients. Interleukin 12 (IL-12) is a pleiotropic cytokine that drives naïve T cells towards a TH1 phenotype, activates NK cells and cytotoxic T cells, and strongly induces the expression of IFNγ by multiple cell types, making it an attractive pro-inflammatory cytokine for cancer immunotherapy. However, despite its demonstrated clinical benefits, poor pharmacokinetic properties and dose-limiting toxicities after systemic administration have greatly limited the use of IL-12 in the clinic. WTX-330 is a novel IL-12 pro-drug that is designed to harness the dysregulated protease activity of tumors to selectively deliver fully active IL-12 to the tumor microenvironment (TME). WTX-330 consists of wild-type IL-12 tethered to a high affinity antibody blockade domain and a half-life extension (HLE) domain via tumor protease-sensitive linkers. Following systemic administration, WTX-330 circulates as an inactive prodrug that is unable to bind to IL-12 receptors in normal tissues. When WTX-330 enters the tumor however, proteases found in the TME cleave the protease-sensitive linkers, releasing fully active IL-12 selectively in the tumor. WTX-330 is highly efficacious in murine syngeneic tumor models, leading to complete, CD8+ T cell dependent tumor regressions when MC38 tumor bearing mice were treated with a murine surrogate of WTX-330. Importantly, while murine WTX-330 was well tolerated by the mice, equimolar amounts of wild-type IL-12 was not, highlighting the tumor selective activity of the INDUKINE™ protein. Murine WTX-330 treatment of either MC38 or EMT6 tumor bearing mice increased the frequency of tumor infiltrating polyfunctional CD8+ T cells and activated tumor infiltrating NK cells in both models. In the EMT6 model, Geospatial NanoString analysis revealed significantly more tumor penetration by CD8+ T cells following murine WTX-330 treatment at multiple timepoints and demonstrated that systemic dosing with the IL-12 INDUKINE™ molecule resulted in IL-12 signaling by the tumor infiltrating CD8+ T cells. Furthermore, murine WTX-330 treatment fundamentally reprogrammed the metabolic program of tumor infiltrating CD8+ T cells, increasing both glycolysis and mitochondrial biogenesis, while also increasing TCR signaling and degranulation. Finally, ex vivo incubation of WTX-330 with various primary human tumors led to the release of active IL-12, while WTX-330 was stable in human serum and healthy human primary cells from various tissues. Together, these data support continued development of this innovative IL-12 therapy into clinical testing. Citation Format: Christopher J. Nirschl, Pam Alderhold, Heather R. Brodkin, Connor J. Dwyer, Daniel J. Hicklin, Nesreen Ismail, Andres Salmeron, Cynthia Seidel-Dugan, Philipp Steiner, Zoe Steuert, Jenna Sullivan, William M. Winston. WTX-330 is a conditionally activated IL-12 prodrug that fundamentally reprograms tumor infiltrating CD8+ T cells and drives tumor regression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2055.

Abstract Background: Interleukin-12 is a potent pleiotropic cytokine, but its clinical translation has been hindered by toxicities. To deliver IL-12 to tumors with high spatial and temporal precision while minimizing off-tumor effects, we have developed an ultra-pH sensitive nanoparticle platform - ON-BOARD - that shields payloads from systemic exposure and targets solid tumors by responding to tumor acidity. Herein, we report the preclinical efficacy and safety characterization of ONM-412, an ON-BOARD nanoparticle encapsulated IL-12Fc fusion protein, and muONM-412, an encapsulated murine IL-12Fc. Methods: Properties and stability profiles of ONM-412 were characterized. pH-specific bioactivity was determined in cell-based reporter and IFNγ induction assays while the activation of ONM-412 was compared to a protease-cleavable IL-12 prodrug. Efficacy and tolerability of muONM-412 were studied in vivo after intravenous injection in mice. Pharmacodynamic response was evaluated by measuring cytokine levels in plasma and tissue, and the changes in tumor immune microenvironment were characterized. Toxicity was measured by body weight loss, systemic cytokine levels and clinical chemistry. Anti-tumor efficacy of muONM-412 was evaluated in MC38 tumor-bearing mice. The safety and tolerability of ONM-412 is also undergoing evaluation in a toxicology study with cynomolgus monkeys. Body weight, hematology, clinical chemistry and urine analysis were performed. Results: ONM-412 showed high encapsulation efficiency (>85%) in uniformly distributed particles (Dh<50nm) with 6-month on-going shelf-life stability. pH-specific release was confirmed in vitro with a >100-fold activation window between the acid-activated and intact formulations by an HEK reporter assay and an IFNγ induction assay. ONM-412 showed rapid and complete recovery of IL-12 bioactivity in <10 minutes after acid-activation while MMP demasking of a prodrug required overnight incubation and compromised potency. In vivo, mice treated with muONM-412 demonstrated significantly improved tolerability compared to unencapsulated IL-12Fc: body weight loss was reduced, no liver toxicity was observed, and plasma IFNγ levels were >1,000-fold lower. muONM-412 induced tumor immune remodeling, with increased infiltration by IFNγ+ and GzmB+ CD8 T and NK cells, and demonstrated strong dose-responsive anti-tumor efficacy in MC38 tumor-bearing animals. Preliminary results from an on-going study in cynomolgus monkeys suggest ONM-412 is well-tolerated at equivalent doses to those that induced maximum antitumor response in mice. Conclusions: ONM-412 significantly improved tolerability over unencapsulated IL-12Fc and showed potent anti-tumor efficacy in mice. It was well-tolerated in mice and non-human primates, showing potential for clinical translation. Citation Format: Qingtai Su, Stephen Gutowski, Austin Burcham, Bhargavi Allu, Zirong Chen, Fiona Stavros, Ruolan Han, Jason B. Miller, Tian Zhao. Preclinical characterization of ONM-412, an ultra-pH sensitive nanoparticle encapsulated IL-12 fusion protein [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB438.

La maladie d’Alzheimer (MA) est une maladie neurodégénérative multifactorielle encore mal comprise. Les médicaments actuellement utilisés contre la MA, principalement des inhibiteurs de cholinestérases (IChE), sont considérés comme ayant un service médical rendu insuffisant et sont responsables d’effets secondaires délétères. Les ChE suscitent toutefois un regain d’intérêt grâce à la découverte du rôle de chaperon joué dans la pathogenèse de la MA. Ces enzymes pourraient également servir de protéine d'activation pour les promédicaments pléiotropes. En effet, l'inhibition des ChE centrales par des molécules possédant un groupement carbamate, conçus pour passer la barrière hématoencéphalique, et capables de se lier de manière covalente à l'enzyme permettrait de libérer des métabolites actifs dans le cerveau. Ceci pourrait constituer une approche plus efficace sur le plan clinique, qui en permettrait de diminuer les effets secondaires périphériques.Cette thèse a permis d’ouvrir de nouvelles voies de synthèse et a conduit à des études in vitro et in vivo de promédicaments pléiotropes ciblant à la fois l’AChE ou la BuChE et une autre cible thérapeutique telle que les récepteurs sérotoninergiques 5-HT4 et / ou 5-HT6, mais aussi l’étude de composés innovants : les ligands autoimmolables pléiotropes.Cette polyactivité pourrait apporter aux patients atteints de MA de réels bénéfices thérapeutiques à la fois symptomatiques et curatifs, ainsi qu’une relative innocuité
Alzheimer’s disease (AD) is a multifactorial neurodegenerative disease which is still poorly understood. The drugs currently used against AD, mainly cholinesterase inhibitors (ChEI), are considered clinically insufficient and are responsible for deleterious side effects. ChE are, however, currently receiving renewed interest through the discovery of a chaperone role played in the pathogenesis of AD. But ChE could also serve as an activating protein for pleiotropic prodrugs. Indeed, inhibiting central ChE with brain-penetrating designed carbamates which are able to covalently bind to the enzyme and to concomitantly liberate active metabolites in the brain could constitute a clinically more efficient approach which, additionally, is less likely to cause peripheral side effects.This thesis has opened up new synthetic pathways, coupled with in vitro and in vivo studies of pleiotropic prodrugs targeting both AChE and BuChE with another therapeutic target such as 5-HT4 and / or 5-HT6 serotoninergic receptors. But also the study new compounds very interesting and never yet describes: pleiotropic self-immolative linkers.This plural activity could bring to AD patients effective, relatively safe, symptomatic and disease-modifying therapeutic benefits

Des études ont montré que les personnes atteintes de syndrome de Down (SD) ou trisomie 21 présentent un risque plus élevé de développer une démence de type maladie d’Alzheimer (MA). En effet, certaines cibles thérapeutiques communes ont été retrouvées dans ces deux maladies multifactorielles, pour lesquelles aucun traitement efficace n’existe à l’heure actuelle. Afin de traiter simultanément ces origines communes, l'approche des ligands pléiotropes multi-cibles (MTDLs) semble prometteuse. Ces composés regroupent dans une structure unique plusieurs activités biologiques ciblant diverses causes moléculaires impliquées dans la maladie. L’objectif est d’obtenir un effet synergique et de diminuer les effets indésirables dans un contexte de maladie chronique nécessitant un traitement à vie. Au cours de cette thèse, de nouvelles voies de synthèse chimique ont été optimisées pour obtenir une vingtaine de promédicaments pléiotropes. Ces composés ont montré des activités in vitro prometteuses sur les cholinestérases, les récepteurs sérotoninergiques, les récepteurs adrénergiques et la protéine HMGB1, quatre cibles importantes pour la MA et/ou associée au SD. Le mécanisme d'inhibition des cholinestérases et l'effet des promédicaments sur un modèle cellulaire ont été évalués. Les paramètres de pharmacopotentialité ont également été déterminés pour identifier la voie d’administration des promédicaments. Ces études ont fourni des données initiales sur les relations structure-activité (RSA) pour les trois cibles, ce qui nous a permis d'identifier le meilleur candidat pour une administration intranasale dans les modèles murins de la MA
Studies have shown that people with Down's syndrome (DS) or trisomy 21 have a higher risk of developing dementia due to Alzheimer's disease (AD). In fact, certain common therapeutic targets have been identified in these two multifactorial diseases, for which no effective treatment currently exists. In order to simultaneously treat these common origins, the approach of multi-target directed ligands (MTDLs) seems promising. These compounds combine in a single structure several biological activities targeting various molecular causes involved in the disease. The aim is to achieve a synergistic effect and reduce side effects in the context of a chronic disease requiring lifelong treatment. During this work, chemical synthesis routes have been optimized to obtain some twenty pleiotropic prodrugs. These compounds have shown promising in vitro activity on cholinesterases, serotonin receptors, adrenergic receptors or HMGB1 protein, four important targets in AD and/or associated with DS. The inhibition mechanism of cholinesterases and the effect of prodrugs on cellular model were evaluated. Permeability and druggability parameters were also determined to identify prodrugs administration route. These studies provided initial structure-activity relationship (SAR) data for the three targets, enabling us to identify the most promising candidate for in vivo studies in AD mice through intranasal administration