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Antibacterial agents target the products of essential genes but rarely achieve complete target inhibition. Thus, the all-or-none definition of essentiality afforded by traditional genetic approaches fails to discern the most attractive bacterial targets: those whose incomplete inhibition results in major fitness costs. In contrast, gene "vulnerability" is a continuous, quantifiable trait that relates the magnitude of gene inhibition to the effect on bacterial fitness. We developed a CRISPR interference-based functional genomics method to systematically titrate gene expression in Mycobacterium tuberculosis (Mtb) and monitor fitness outcomes. We identified highly vulnerable genes in various processes, including novel targets unexplored for drug discovery. Equally important, we identified invulnerable essential genes, potentially explaining failed drug discovery efforts. Comparison of vulnerability between the reference and a hypervirulent Mtb isolate revealed incomplete conservation of vulnerability and that differential vulnerability can predict differential antibacterial susceptibility. Our results quantitatively redefine essential bacterial processes and identify high-value targets for drug development.
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Regulación Bacteriana de la Expresión Génica , Genoma Bacteriano , Mycobacterium tuberculosis/genética , Aminoacil-ARNt Sintetasas/metabolismo , Antituberculosos/farmacología , Teorema de Bayes , Evolución Biológica , Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas/genética , Regulación Bacteriana de la Expresión Génica/efectos de los fármacos , Silenciador del Gen/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Mycobacterium tuberculosis/efectos de los fármacos , ARN Guía de Kinetoplastida/genéticaRESUMEN
The cellular thermal shift assay (CETSA) is a biophysical technique allowing direct studies of ligand binding to proteins in cells and tissues. The proteome-wide implementation of CETSA with mass spectrometry detection (MS-CETSA) has now been successfully applied to discover targets for orphan clinical drugs and hits from phenotypic screens, to identify off-targets, and to explain poly-pharmacology and drug toxicity. Highly sensitive multidimensional MS-CETSA implementations can now also access binding of physiological ligands to proteins, such as metabolites, nucleic acids, and other proteins. MS-CETSA can thereby provide comprehensive information on modulations of protein interaction states in cellular processes, including downstream effects of drugs and transitions between different physiological cell states. Such horizontal information on ligandmodulation in cells is largely orthogonal to vertical information on the levels of different proteins and therefore opens novel opportunities to understand operational aspects of cellular proteomes.
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Desarrollo de Medicamentos/métodos , Proteoma/metabolismo , Ensayo de Cambio de Movilidad Electroforética , Humanos , Ligandos , Espectrometría de Masas , Unión Proteica , Proteoma/química , ProteómicaRESUMEN
Cyclin-dependent kinase 9 (CDK9) promotes transcriptional elongation through RNAPII pause release. We now report that CDK9 is also essential for maintaining gene silencing at heterochromatic loci. Through a live cell drug screen with genetic confirmation, we discovered that CDK9 inhibition reactivates epigenetically silenced genes in cancer, leading to restored tumor suppressor gene expression, cell differentiation, and activation of endogenous retrovirus genes. CDK9 inhibition dephosphorylates the SWI/SNF protein BRG1, which contributes to gene reactivation. By optimization through gene expression, we developed a highly selective CDK9 inhibitor (MC180295, IC50 = 5 nM) that has broad anti-cancer activity in vitro and is effective in in vivo cancer models. Additionally, CDK9 inhibition sensitizes to the immune checkpoint inhibitor α-PD-1 in vivo, making it an excellent target for epigenetic therapy of cancer.
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Quinasa 9 Dependiente de la Ciclina/metabolismo , Animales , Línea Celular Tumoral , Quinasa 9 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 9 Dependiente de la Ciclina/genética , ADN Helicasas/genética , ADN Helicasas/metabolismo , Metilación de ADN , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Leucocitos Mononucleares/citología , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos NOD , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-myc/metabolismo , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacología , Relación Estructura-Actividad , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
Tumor-agnostic therapies represent a paradigm shift in oncology by altering the traditional means of characterizing tumors based on their origin or location. Instead, they zero in on specific genetic anomalies responsible for fueling malignant growth. The watershed moment for tumor-agnostic therapies arrived in 2017, with the US Food and Drug Administration's historic approval of pembrolizumab, an immune checkpoint inhibitor. This milestone marked the marriage of genomics and immunology fields, as an immunotherapeutic agent gained approval based on genomic biomarkers, specifically, microsatellite instability-high or mismatch repair deficiency (dMMR). Subsequently, the approval of NTRK inhibitors, designed to combat NTRK gene fusions prevalent in various tumor types, including pediatric cancers and adult solid tumors, further underscored the potential of tumor-agnostic therapies. The US Food and Drug Administration approvals of targeted therapies (BRAF V600E, RET fusion), immunotherapies (tumor mutational burden ≥10 mutations per megabase, dMMR) and an antibody-drug conjugate (Her2-positive-immunohistochemistry 3+ expression) with pan-cancer efficacy have continued, offering newfound hope to patients grappling with advanced solid tumors that harbor particular biomarkers. In this comprehensive review, the authors delve into the expansive landscape of tissue-agnostic targets and drugs, shedding light on the rationale underpinning this approach, the hurdles it faces, presently approved therapies, voices from the patient advocacy perspective, and the tantalizing prospects on the horizon. This is a welcome advance in oncology that transcends the boundaries of histology and location to provide personalized options.
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PARPs catalyze ADP-ribosylation-a post-translational modification that plays crucial roles in biological processes, including DNA repair, transcription, immune regulation, and condensate formation. ADP-ribosylation can be added to a wide range of amino acids with varying lengths and chemical structures, making it a complex and diverse modification. Despite this complexity, significant progress has been made in developing chemical biology methods to analyze ADP-ribosylated molecules and their binding proteins on a proteome-wide scale. Additionally, high-throughput assays have been developed to measure the activity of enzymes that add or remove ADP-ribosylation, leading to the development of inhibitors and new avenues for therapy. Real-time monitoring of ADP-ribosylation dynamics can be achieved using genetically encoded reporters, and next-generation detection reagents have improved the precision of immunoassays for specific forms of ADP-ribosylation. Further development and refinement of these tools will continue to advance our understanding of the functions and mechanisms of ADP-ribosylation in health and disease.
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ADP-Ribosilación , Poli(ADP-Ribosa) Polimerasas , Poli(ADP-Ribosa) Polimerasas/metabolismo , Procesamiento Proteico-Postraduccional , Adenosina Difosfato Ribosa/metabolismoRESUMEN
Neurohypophysial peptides are ancient and evolutionarily highly conserved neuropeptides that regulate many crucial physiological functions in vertebrates and invertebrates. The human neurohypophysial oxytocin/vasopressin (OT/VP) signaling system with its four receptors has become an attractive drug target for a variety of diseases, including cancer, pain, cardiovascular indications, and neurological disorders. Despite its promise, drug development faces hurdles, including signaling complexity, selectivity and off-target concerns, translational interspecies differences, and inefficient drug delivery. In this review we dive into the complexity of the OT/VP signaling system in health and disease, provide an overview of relevant pharmacological probes, and discuss the latest trends in therapeutic lead discovery and drug development.
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Oxitocina , Vasopresinas , Animales , Humanos , Receptores de VasopresinasRESUMEN
Tinnitus is a pervasive public health issue that affects â¼15% of the United States population. Similar estimates have also been shown on a global scale, with similar prevalence found in Europe, Asia, and Africa. The severity of tinnitus is heterogeneous, ranging from mildly bothersome to extremely disruptive. In the United States, â¼10-20% of individuals who experience tinnitus report symptoms that severely reduce their quality of life. Due to the huge personal and societal burden, in the last 20 yr a concerted effort on basic and clinical research has significantly advanced our understanding and treatment of this disorder. Yet, neither full understanding, nor cure exists. We know that tinnitus is the persistent involuntary phantom percept of internally generated nonverbal indistinct noises and tones, which in most cases is initiated by acquired hearing loss and maintained only when this loss is coupled with distinct neuronal changes in auditory and extra-auditory brain networks. Yet, the exact mechanisms and patterns of neural activity that are necessary and sufficient for the perceptual generation and maintenance of tinnitus remain incompletely understood. Combinations of animal model and human research will be essential in filling these gaps. Nevertheless, the existing progress in investigating the neurophysiological mechanisms has improved current treatment and highlighted novel targets for drug development and clinical trials. The aim of this review is to thoroughly discuss the current state of human and animal tinnitus research, outline current challenges, and highlight new and exciting research opportunities.
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Neurociencias , Acúfeno/fisiopatología , Acúfeno/terapia , Animales , Modelos Animales de Enfermedad , Pérdida Auditiva/etiología , Pérdida Auditiva/fisiopatología , Humanos , Calidad de Vida , Acúfeno/complicacionesRESUMEN
Infections caused by malaria parasites place an enormous burden on the world's poorest communities. Breakthrough drugs with novel mechanisms of action are urgently needed. As an organism that undergoes rapid growth and division, the malaria parasite Plasmodium falciparum is highly reliant on protein synthesis, which in turn requires aminoacyl-tRNA synthetases (aaRSs) to charge tRNAs with their corresponding amino acid. Protein translation is required at all stages of the parasite life cycle; thus, aaRS inhibitors have the potential for whole-of-life-cycle antimalarial activity. This review focuses on efforts to identify potent plasmodium-specific aaRS inhibitors using phenotypic screening, target validation, and structure-guided drug design. Recent work reveals that aaRSs are susceptible targets for a class of AMP-mimicking nucleoside sulfamates that target the enzymes via a novel reaction hijacking mechanism. This finding opens up the possibility of generating bespoke inhibitors of different aaRSs, providing new drug leads.
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Aminoacil-ARNt Sintetasas , Antimaláricos , Malaria , Humanos , Antimaláricos/farmacología , Antimaláricos/uso terapéutico , Aminoacil-ARNt Sintetasas/química , Aminoacil-ARNt Sintetasas/genética , Aminoacil-ARNt Sintetasas/metabolismo , Plasmodium falciparum/genética , Malaria/tratamiento farmacológico , ARN de Transferencia/genética , ARN de Transferencia/metabolismo , ARN de Transferencia/uso terapéuticoRESUMEN
The nucleolus is the site of ribosome biogenesis, one of the most resource-intensive processes in eukaryotic cells. Accordingly, nucleolar morphology and activity are highly responsive to growth signaling and nucleolar insults which are collectively included in the actively evolving concept of nucleolar stress. Importantly, nucleolar alterations are a prominent feature of multiple human pathologies, including cancer and neurodegeneration, as well as being associated with aging. The past decades have seen numerous attempts to isolate compounds targeting different facets of nucleolar activity. We provide an overview of therapeutic opportunities for targeting nucleoli in different pathologies and currently available therapies.
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Neoplasias , Ribosomas , Humanos , Nucléolo Celular/patología , Neoplasias/tratamiento farmacológico , Neoplasias/patología , EnvejecimientoRESUMEN
Cannabis is one of the oldest and widely used substances in the world. Cannabinoids within the cannabis plant, known as phytocannabinoids, mediate cannabis' effects through interactions with the body's endogenous cannabinoid system. This endogenous system, the endocannabinoid system, has important roles in physical and mental health. These roles point to the potential to develop cannabinoids as therapeutic agents, while underscoring the risks related to interfering with the endogenous system during non-medical use. This scoping narrative review synthesizes the current evidence for both the therapeutic and adverse effects of the major (i.e., Δ9-tetrahydrocannabinol and cannabidiol) and lesser studied minor phytocannabinoids, from nonclinical to clinical research. We pay particular attention to the areas where evidence is well-established, including analgesic effects after acute exposures and neurocognitive risks after acute and chronic use. In addition, drug development considerations for cannabinoids as therapeutic agents within the United States are reviewed. The proposed clinical study design considerations encourage methodological standards for greater scientific rigor and reproducibility, ultimately, to extend our knowledge of the risks and benefits of cannabinoids for patients and providers. Significance Statement This work provides a review of prior research related to phytocannabinoids, including therapeutic potential and known risks in the context of drug development within the United States. We also provide study design considerations for future cannabinoid drug development.
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The purpose of this review is to summarize essential biological, pharmaceutical and clinical aspects in the field of topically applied medicines that may help scientists when trying to develop new topical medicines. After a brief history of topical drug delivery, a review of the structure and function of the skin, routes of drug absorption and their limitations is then provided. The most prevalent diseases and current topical treatment approaches are then detailed, the organization of which reflects the key disease categories of autoimmune and inflammatory, microbial infections, skin cancers and genetic skin diseases. The complexity of topical product development through to large scale manufacture along with recommended risk mitigation approaches is then highlighted. As such topical treatments are applied externally patient preferences along with the challenges they invoke are then described and finally the future of this field of drug delivery is discussed with the emphasis on areas that are more likely to yield significant improvements over the topical medicines in current use or would expand the range of medicines and diseases treatable by this route of administration. Significance Statement This review of the key aspects the skin, its associated diseases and current treatments along with the intricacies of topical formulation development should be helpful in making judicious decisions about the development of new or improved topical medicines. These aspects include the choices of the active ingredients, formulations, the target patient populations preferences and limitations and the future with regards to new skin diseases and topical medicine approaches.
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Recent breakthroughs in human genetics and in information technologies have markedly expanded our understanding at the molecular level of the response to drugs, i.e. pharmacogenetics (PGx), across therapy areas. This review is restricted to PGx for cardiovascular (CV) drugs. First, we examined the PGx information in the labels approved by regulatory agencies in Europe, Japan and North America, and related recommendations from expert panels. Out of 221 marketed CV drugs, 36 had PGx information in their labels approved by one or more agencies. The level of annotations and recommendations varied markedly between agencies and expert panels. Clopidogrel is the only CV drug with consistent PGx recommendation (i.e., "actionable"). This situation prompted us to dissect the steps from discovery of a PGx association to clinical translation. We found 101 genome-wide association studies which investigated the response to CV drugs or drug classes. These studies reported significant associations for 48 PGx traits mapping to 306 genes. Six of these 306 genes are mentioned in the corresponding PGx labels or recommendations for CV drugs. Genomic analyses also highlighted the wide between-population differences in risk allele frequencies, and the individual load of actionable PGx variants. Given high attrition rate and the long road to clinical translation, additional work is warranted to identify and validate PGx variants for more CV drugs across diverse populations and to demonstrate the utility of PGx testing. To that end, pre-emptive PGx combining genomic profiling with electronic medical records opens unprecedented opportunities to improve healthcare, for CV disease and beyond. Significance Statement Despite spectacular breakthroughs in human molecular genetics and information technologies, consistent evidence supporting pharmacogenetic (PGx) testing in the cardiovascular area is limited to few drugs. Additional work is warranted to discover and validate new PGx markers and demonstrate their utility. Pre-emptive PGx combining genomic profiling with electronic medical records opens unprecedented opportunities to improve healthcare, for cardiovascular disease and beyond.
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Over four decades of research support the link between Alzheimer's disease (AD) and somatostatin (somatotropin-releasing inhibitory factor, SRIF). SRIF and SRIF-expressing neurons play an essential role in brain function, modulating hippocampal activity and memory formation. Loss of SRIF and SRIF-expressing neurons in the brain rests at the center of a series of interdependent pathological events driven by amyloid-beta peptide (Aß), culminating in cognitive decline and dementia. The connection between the SRIF and AD further extends to the neuropsychiatric symptoms, seizure activity, and inflammation. Whereas, preclinical AD investigations show SRIF or SRIF-receptor agonist administration capable of enhancing cognition. SRIF receptor subtype-4 activation in particular presents unique attributes, with the potential to mitigate learning and memory decline, reduce comorbid symptoms, and enhance enzymatic degradation of Aß in the brain. Here we review the links between SRIF and AD, along with the therapeutic implications. Significance Statement Somatostatin and somatostatin-expressing neurons in the brain are extensively involved in cognition. Loss of somatostatin and somatostatin-expressing neurons in Alzheimer's disease rests at the center of a series of interdependent pathological events contributing to cognitive decline and dementia. Targeting somatostatin mediated processes has significant therapeutic potential for the treatment of Alzheimer's disease.
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Our knowledge of the roles of individual cytochrome P450 (P450, CYP) enzymes in drug metabolism has developed considerably in the past 30 years, and this base has been of considerable use in avoiding serious issues with drug interactions and issues due to variations. Some newer approaches are being considered for "phenotyping" of metabolism reactions with new drug candidates. Endogenous biomarkers are being used for non-invasive estimation of levels of individual P450 enzymes. There is also the matter of some remaining "orphan" P450s, which have yet to be assigned reactions. Practical problems that continue in drug development include predicting drug-drug interactions, predicting the effects of polymorphic and other P450 variations, and evaluating inter-species differences in drug metabolism, particularly in the context of "metabolism in safety testing" (MIST) regulatory issues ("disproportionate (human) metabolites"). Significance Statement Cytochrome P450 enzymes are the major catalysts involved in drug metabolism. The characterization of their individual roles has major implications in drug development and clinical practice.
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Artificial intelligence (AI) powered drug development has received remarkable attention in recent years. It addresses the limitations of traditional experimental methods that are costly and time-consuming. While there have been many surveys attempting to summarize related research, they only focus on general AI or specific aspects such as natural language processing and graph neural network. Considering the rapid advance on computer vision, using the molecular image to enable AI appears to be a more intuitive and effective approach since each chemical substance has a unique visual representation. In this paper, we provide the first survey on image-based molecular representation for drug development. The survey proposes a taxonomy based on the learning paradigms in computer vision and reviews a large number of corresponding papers, highlighting the contributions of molecular visual representation in drug development. Besides, we discuss the applications, limitations and future directions in the field. We hope this survey could offer valuable insight into the use of image-based molecular representation learning in the context of drug development.
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Desarrollo de Medicamentos , Desarrollo de Medicamentos/métodos , Inteligencia Artificial , Humanos , Procesamiento de Imagen Asistido por Computador/métodos , Redes Neurales de la Computación , Aprendizaje Automático , Descubrimiento de Drogas/métodosRESUMEN
Cyclic peptides offer a range of notable advantages, including potent antibacterial properties, high binding affinity and specificity to target molecules, and minimal toxicity, making them highly promising candidates for drug development. However, a comprehensive database that consolidates both synthetically derived and naturally occurring cyclic peptides is conspicuously absent. To address this void, we introduce CyclicPepedia (https://www.biosino.org/iMAC/cyclicpepedia/), a pioneering database that encompasses 8744 known cyclic peptides. This repository, structured as a composite knowledge network, offers a wealth of information encompassing various aspects of cyclic peptides, such as cyclic peptides' sources, categorizations, structural characteristics, pharmacokinetic profiles, physicochemical properties, patented drug applications, and a collection of crucial publications. Supported by a user-friendly knowledge retrieval system and calculation tools specifically designed for cyclic peptides, CyclicPepedia will be able to facilitate advancements in cyclic peptide drug development.
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Bases del Conocimiento , Péptidos Cíclicos , Péptidos Cíclicos/química , Bases de Datos de ProteínasRESUMEN
Melanocortin receptors have emerged as important targets with a very unusual versatility, as their widespread distribution on multiple tissues (e.g. skin, adrenal glands, brain, immune cells, exocrine glands) together with the variety of physiological processes they control (pigmentation, cortisol release, satiety mechanism, inflammation, secretions), place this family of receptors as genuine therapeutic targets for many disorders. This review focuses in the journey of the development of melanocortin receptors as therapeutic targets from the discovery of their existence in the early 1990 s to the approval of the first few drugs of this class. Two major areas of development characterise the current state of melanocortin drug development: their role in obesity, recently culminated with the approval of setmelanotide, and their potential for the treatment of chronic inflammatory and autoimmune diseases like rheumatoid arthritis, multiple sclerosis or fibrosis. The pro-resolving nature of these drugs offers the advantage of acting by mimicking the way our body naturally resolves inflammation, expecting fewer side effects and a more balanced (i.e. non-immunosuppressive) response from them. Here we also review the approaches followed for the design and development of novel compounds, the importance of the GPCR nature of these receptors in the process of drug development, therapeutic value, current challenges and successes, and the potential for the implementation of precision medicine approaches through the incorporation of genetics advances.
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Artritis Reumatoide , Melanocortinas , Humanos , Proteínas Portadoras , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Melanocortinas/metabolismo , Receptores de Melanocortina/genética , Receptores de Melanocortina/metabolismoRESUMEN
Monoclonal antibodies (mAbs) have successfully been developed for the treatment of a wide range of diseases. The clinical success of mAbs does not solely rely on optimal potency and safety but also require good biophysical properties to ensure a high developability potential. In particular, nonspecific interactions are a key developability parameter to monitor during discovery and development. Despite an increased focus on the detection of nonspecific interactions, their underlying physicochemical origins remain poorly understood. Here, we employ solution-based microfluidic technologies to characterize a set of clinical-stage mAbs and their interactions with commonly used nonspecificity ligands to generate nonspecificity fingerprints, providing quantitative data on the underlying physical chemistry. Furthermore, the solution-based analysis enables us to measure binding affinities directly, and we evaluate the contribution of avidity in nonspecific binding by mAbs. We find that avidity can increase the apparent affinity by two orders of magnitude. Notably, we find that a subset of these highly developed mAbs show nonspecific electrostatic interactions, even at physiological pH and ionic strength, and that they can form microscale particles with charge-complementary polymers. The group of mAb constructs flagged here for nonspecificity are among the worst performers in independent reports of surface and column-based screens. The solution measurements improve on the state-of-the-art by providing a stand-alone result for individual mAbs without the need to benchmark against cohort data. Based on our findings, we propose a quantitative solution-based nonspecificity score, which can be integrated in the development workflow for biological therapeutics and more widely in protein engineering.
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Anticuerpos Monoclonales , Ingeniería de Proteínas , HumanosRESUMEN
Over recent decades, the global burden of fungal disease has expanded dramatically. It is estimated that fungal disease kills approximately 1.5 million individuals annually; however, the true worldwide burden of fungal infection is thought to be higher due to existing gaps in diagnostics and clinical understanding of mycotic disease. The development of resistance to antifungals across diverse pathogenic fungal genera is an increasingly common and devastating phenomenon due to the dearth of available antifungal classes. These factors necessitate a coordinated response by researchers, clinicians, public health agencies, and the pharmaceutical industry to develop new antifungal strategies, as the burden of fungal disease continues to grow. This review provides a comprehensive overview of the new antifungal therapeutics currently in clinical trials, highlighting their spectra of activity and progress toward clinical implementation. We also profile up-and-coming intracellular proteins and pathways primed for the development of novel antifungals targeting their activity. Ultimately, we aim to emphasize the importance of increased investment into antifungal therapeutics in the current continually evolving landscape of infectious disease.
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Antifúngicos , Micosis , Humanos , Antifúngicos/farmacología , Antifúngicos/uso terapéutico , Micosis/tratamiento farmacológico , Micosis/microbiología , Farmacorresistencia FúngicaRESUMEN
SUMMARYThe human intestinal tract harbors a profound variety of microorganisms that live in symbiosis with the host and each other. It is a complex and highly dynamic environment whose homeostasis directly relates to human health. Dysbiosis of the gut microbiota and polymicrobial biofilms have been associated with gastrointestinal diseases, including irritable bowel syndrome, inflammatory bowel diseases, and colorectal cancers. This review covers the molecular composition and organization of intestinal biofilms, mechanistic aspects of biofilm signaling networks for bacterial communication and behavior, and synergistic effects in polymicrobial biofilms. It further describes the clinical relevance and diseases associated with gut biofilms, the role of biofilms in antimicrobial resistance, and the intestinal host defense system and therapeutic strategies counteracting biofilms. Taken together, this review summarizes the latest knowledge and research on intestinal biofilms and their role in gut disorders and provides directions toward the development of biofilm-specific treatments.