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1.
Biochemistry ; 62(3): 601-623, 2023 02 07.
Artículo en Inglés | MEDLINE | ID: mdl-35856839

RESUMEN

Targeted protein degradation is a rapidly exploding drug discovery strategy that uses small molecules to recruit disease-causing proteins for rapid destruction mainly via the ubiquitin-proteasome pathway. It shows great potential for treating diseases such as cancer and infectious, inflammatory, and neurodegenerative diseases, especially for those with "undruggable" pathogenic protein targets. With the recent rise of the "molecular glue" type of protein degraders, which tighten and simplify the connection of an E3 ligase with a disease-causing protein for ubiquitination and subsequent degradation, new therapies for unmet medical needs are being designed and developed. Here we use data from the CAS Content Collection and the publication landscape of recent research on targeted protein degraders to provide insights into these molecules, with a special focus on molecular glues. We also outline the advantages of the molecular glues and summarize the advances in drug discovery practices for molecular glue degraders. We further provide a thorough review of drug candidates in targeted protein degradation through E3 ligase recruitment. Finally, we highlight the progression of molecular glues in drug discovery pipelines and their targeted diseases. Overall, our paper provides a comprehensive reference to support the future development of molecular glues in medicine.


Asunto(s)
Proteínas , Ubiquitina-Proteína Ligasas , Proteolisis , Proteínas/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitinación , Descubrimiento de Drogas , Complejo de la Endopetidasa Proteasomal/metabolismo
2.
Bioconjug Chem ; 34(6): 941-960, 2023 06 21.
Artículo en Inglés | MEDLINE | ID: mdl-37162501

RESUMEN

Lipid nanoparticles (LNPs) have been recognized as efficient vehicles to transport a large variety of therapeutics. Currently in the spotlight as important constituents of the COVID-19 mRNA vaccines, LNPs play a significant role in protecting and transporting mRNA to cells. As one of their key constituents, polyethylene glycol (PEG)-lipid conjugates are important in defining LNP physicochemical characteristics and biological activity. PEGylation has proven particularly efficient in conferring longer systemic circulation of LNPs, thus greatly improving their pharmacokinetics and efficiency. Along with revealing the benefits of PEG conjugates, studies have revealed unexpected immune reactions against PEGylated nanocarriers such as accelerated blood clearance (ABC), involving the production of anti-PEG antibodies at initial injection, which initiates accelerated blood clearance upon subsequent injections, as well as a hypersensitivity reaction referred to as complement activation-related pseudoallergy (CARPA). Further, data have been accumulated indicating consistent yet sometimes controversial correlations between various structural parameters of the PEG-lipids, the properties of the PEGylated LNPs, and the magnitude of the observed adverse effects. Detailed knowledge and comprehension of such correlations are of foremost importance in the efforts to diminish and eliminate the undesirable immune reactions and improve the safety and efficiency of the PEGylated medicines. Here, we present an overview based on analysis of data from the CAS Content Collection regarding the PEGylated LNP immunogenicity and overall safety concerns. A comprehensive summary has been compiled outlining how various structural parameters of the PEG-lipids affect the immune responses and activities of the LNPs, with regards to their efficiency in drug delivery. This Review is thus intended to serve as a helpful resource in understanding the current knowledge in the field, in an effort to further solve the remaining challenges and to achieve full potential.


Asunto(s)
COVID-19 , Nanopartículas , Humanos , Liposomas/química , Polietilenglicoles/química , Nanopartículas/química , Lípidos/química
3.
Bioconjug Chem ; 34(11): 1951-2000, 2023 11 15.
Artículo en Inglés | MEDLINE | ID: mdl-37821099

RESUMEN

Antibody-drug conjugates (ADCs) are targeted immunoconjugate constructs that integrate the potency of cytotoxic drugs with the selectivity of monoclonal antibodies, minimizing damage to healthy cells and reducing systemic toxicity. Their design allows for higher doses of the cytotoxic drug to be administered, potentially increasing efficacy. They are currently among the most promising drug classes in oncology, with efforts to expand their application for nononcological indications and in combination therapies. Here we provide a detailed overview of the recent advances in ADC research and consider future directions and challenges in promoting this promising platform to widespread therapeutic use. We examine data from the CAS Content Collection, the largest human-curated collection of published scientific information, and analyze the publication landscape of recent research to reveal the exploration trends in published documents and to provide insights into the scientific advances in the area. We also discuss the evolution of the key concepts in the field, the major technologies, and their development pipelines with company research focuses, disease targets, development stages, and publication and investment trends. A comprehensive concept map has been created based on the documents in the CAS Content Collection. We hope that this report can serve as a useful resource for understanding the current state of knowledge in the field of ADCs and the remaining challenges to fulfill their potential.


Asunto(s)
Antineoplásicos , Inmunoconjugados , Neoplasias , Humanos , Inmunoconjugados/uso terapéutico , Antineoplásicos/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Neoplasias/tratamiento farmacológico
4.
ACS Chem Neurosci ; 15(1): 1-30, 2024 Jan 03.
Artículo en Inglés | MEDLINE | ID: mdl-38095562

RESUMEN

Aging is a dynamic, time-dependent process that is characterized by a gradual accumulation of cell damage. Continual functional decline in the intrinsic ability of living organisms to accurately regulate homeostasis leads to increased susceptibility and vulnerability to diseases. Many efforts have been put forth to understand and prevent the effects of aging. Thus, the major cellular and molecular hallmarks of aging have been identified, and their relationships to age-related diseases and malfunctions have been explored. Here, we use data from the CAS Content Collection to analyze the publication landscape of recent aging-related research. We review the advances in knowledge and delineate trends in research advancements on aging factors and attributes across time and geography. We also review the current concepts related to the major aging hallmarks on the molecular, cellular, and organismic level, age-associated diseases, with attention to brain aging and brain health, as well as the major biochemical processes associated with aging. Major age-related diseases have been outlined, and their correlations with the major aging features and attributes are explored. We hope this review will be helpful for apprehending the current knowledge in the field of aging mechanisms and progression, in an effort to further solve the remaining challenges and fulfill its potential.


Asunto(s)
Senescencia Celular , Senescencia Celular/fisiología , Factores de Edad
5.
ACS Chem Neurosci ; 15(3): 408-446, 2024 02 07.
Artículo en Inglés | MEDLINE | ID: mdl-38214973

RESUMEN

Aging is typified by a gradual loss of physiological fitness and accumulation of cellular damage, leading to deteriorated functions and enhanced vulnerability to diseases. Antiaging research has a long history throughout civilization, with many efforts put forth to understand and prevent the effects of aging. Multiple strategies aiming to promote healthy aging and extend the lifespan have been developed including lifestyle adjustments, medical treatments, and social programs. A multitude of antiaging medicines and remedies have also been explored. Here, we use data from the CAS Content Collection to analyze the publication landscape of recent research related to antiaging strategies and treatments. We review the recent advances and delineate trends in research headway of antiaging knowledge and practice across time, geography, and development pipelines. We further assess the state-of-the-art antiaging approaches and explore their correlations with age-related diseases. The landscape of antiaging drugs has been outlined and explored. Well-recognized and novel, currently evaluated antiaging agents have also been summarized. Finally, we review clinical applications of antiaging products with their development pipelines. The objective of this review is to summarize current knowledge on preventive strategies and treatment remedies in the field of aging, to outline challenges and evaluate growth opportunities, in order to further efforts to solve the problems that remain.

6.
ACS Pharmacol Transl Sci ; 7(3): 586-613, 2024 Mar 08.
Artículo en Inglés | MEDLINE | ID: mdl-38481702

RESUMEN

Cancer is one of the leading causes of death worldwide. Early cancer detection is critical because it can significantly improve treatment outcomes, thus saving lives, reducing suffering, and lessening psychological and economic burdens. Cancer biomarkers provide varied information about cancer, from early detection of malignancy to decisions on treatment and subsequent monitoring. A large variety of molecular, histologic, radiographic, or physiological entities or features are among the common types of cancer biomarkers. Sizeable recent methodological progress and insights have promoted significant developments in the field of early cancer detection biomarkers. Here we provide an overview of recent advances in the knowledge related to biomolecules and cellular entities used for early cancer detection. We examine data from the CAS Content Collection, the largest human-curated collection of published scientific information, as well as from the biomarker datasets at Excelra, and analyze the publication landscape of recent research. We also discuss the evolution of key concepts and cancer biomarkers development pipelines, with a particular focus on pancreatic and liver cancers, which are known to be remarkably difficult to detect early and to have particularly high morbidity and mortality. The objective of the paper is to provide a broad overview of the evolving landscape of current knowledge on cancer biomarkers and to outline challenges and evaluate growth opportunities, in order to further efforts in solving the problems that remain. The merit of this review stems from the extensive, wide-ranging coverage of the most up-to-date scientific information, allowing unique, unmatched breadth of landscape analysis and in-depth insights.

7.
J Med Chem ; 67(11): 8519-8544, 2024 Jun 13.
Artículo en Inglés | MEDLINE | ID: mdl-38787632

RESUMEN

In the ever-evolving landscape of cancer research, immuno-oncology stands as a beacon of hope, offering novel avenues for treatment. This study capitalizes on the vast repository of immuno-oncology-related scientific documents within the CAS Content Collection, totaling over 350,000, encompassing journals and patents. Through a pioneering approach melding natural language processing with the CAS indexing system, we unveil over 300 emerging concepts, depicted in a comprehensive "Trend Landscape Map". These concepts, spanning therapeutic targets, biomarkers, and types of cancers among others, are hierarchically organized into eight major categories. Delving deeper, our analysis furnishes detailed quantitative metrics showcasing growth trends over the past three years. Our findings not only provide valuable insights for guiding future research endeavors but also underscore the merit of tapping the vast and unparalleled breadth of existing scientific information to derive profound insights.


Asunto(s)
Inmunoterapia , Neoplasias , Humanos , Neoplasias/inmunología , Neoplasias/tratamiento farmacológico , Inmunoterapia/métodos , Oncología Médica/métodos , Procesamiento de Lenguaje Natural
8.
ACS Pharmacol Transl Sci ; 6(7): 943-969, 2023 Jul 14.
Artículo en Inglés | MEDLINE | ID: mdl-37470024

RESUMEN

With the rapid success in the development of mRNA vaccines against COVID-19 and with a number of mRNA-based drugs ahead in the pipelines, mRNA has catapulted to the forefront of drug research, demonstrating its substantial effectiveness against a broad range of diseases. As the recent global pandemic gradually fades, we cannot stop thinking about what the world has gained: the realization and validation of the power of mRNA in modern medicine. A significant amount of research has now been concentrated on developing mRNA drugs and vaccine platforms against infectious and immune diseases, cancer, and other debilitating diseases and has demonstrated encouraging results. Here, based on the CAS Content Collection, we provide a landscape view of the current state, outline trends in the research and development of mRNA therapeutics and vaccines, and highlight some notable patents focusing on mRNA therapeutics, vaccines, and delivery systems. Analysis of diseases disclosed in patents also reveals highly investigated diseases for treatments with these medicines. Finally, we provide information about mRNA therapeutics and vaccines in clinical trials. We hope this Review will be useful for understanding the current knowledge in the field of mRNA medicines and will assist in efforts to solve its remaining challenges and revolutionize the treatment of human diseases.

9.
ACS Chem Neurosci ; 14(10): 1717-1763, 2023 05 17.
Artículo en Inglés | MEDLINE | ID: mdl-37156006

RESUMEN

Gut microbiota includes a vast collection of microorganisms residing within the gastrointestinal tract. It is broadly recognized that the gut and brain are in constant bidirectional communication, of which gut microbiota and its metabolic production are a major component, and form the so-called gut microbiome-brain axis. Disturbances of microbiota homeostasis caused by imbalance in their functional composition and metabolic activities, known as dysbiosis, cause dysregulation of these pathways and trigger changes in the blood-brain barrier permeability, thereby causing pathological malfunctions, including neurological and functional gastrointestinal disorders. In turn, the brain can affect the structure and function of gut microbiota through the autonomic nervous system by regulating gut motility, intestinal transit and secretion, and gut permeability. Here, we examine data from the CAS Content Collection, the largest collection of published scientific information, and analyze the publication landscape of recent research. We review the advances in knowledge related to the human gut microbiome, its complexity and functionality, its communication with the central nervous system, and the effect of the gut microbiome-brain axis on mental and gut health. We discuss correlations between gut microbiota composition and various diseases, specifically gastrointestinal and mental disorders. We also explore gut microbiota metabolites with regard to their impact on the brain and gut function and associated diseases. Finally, we assess clinical applications of gut-microbiota-related substances and metabolites with their development pipelines. We hope this review can serve as a useful resource in understanding the current knowledge on this emerging field in an effort to further solving of the remaining challenges and fulfilling its potential.


Asunto(s)
Microbioma Gastrointestinal , Microbiota , Humanos , Microbioma Gastrointestinal/fisiología , Encéfalo/metabolismo , Sistema Nervioso Central/fisiología , Tracto Gastrointestinal , Microbiota/fisiología
10.
ACS Infect Dis ; 8(3): 422-432, 2022 03 11.
Artículo en Inglés | MEDLINE | ID: mdl-35196007

RESUMEN

Since the beginning of the COVID-19 pandemic caused by SARS-CoV-2, millions of patients have been diagnosed and many of them have died from the disease worldwide. The identification of novel therapeutic targets are of utmost significance for prevention and treatment of COVID-19. SARS-CoV-2 is a single-stranded RNA virus with a 30 kb genome packaged into a membrane-enveloped virion, transcribing several tens of proteins. The belief that the amino acid sequence of proteins determines their 3D structure which, in turn, determines their function has been a central principle of molecular biology for a long time. Recently, it has been increasingly realized, however, that there is a large group of proteins that lack a fixed or ordered 3D structure, yet they exhibit important biological activities─so-called intrinsically disordered proteins and protein regions (IDPs/IDRs). Disordered regions in viral proteins are generally associated with viral infectivity and pathogenicity because they endow the viral proteins the ability to easily and promiscuously bind to host proteins; therefore, the proteome of SARS-CoV-2 has been thoroughly examined for intrinsic disorder. It has been recognized that, in fact, the SARS-CoV-2 proteome exhibits significant levels of structural order, with only the nucleocapsid (N) structural protein and two of the nonstructural proteins being highly disordered. The spike (S) protein of SARS-CoV-2 exhibits significant levels of structural order, yet its predicted percentage of intrinsic disorder is still higher than that of the spike protein of SARS-CoV. Noteworthy, however, even though IDPs/IDRs are not common in the SARS-CoV-2 proteome, the existing ones play major roles in the functioning and virulence of the virus and are thus promising drug targets for rational antiviral drug design. Presented here is a COVID-19 perspective on the intrinsically disordered proteins, summarizing recent results on the SARS-CoV-2 proteome disorder features, their physiological and pathological relevance, and their prominence as prospective drug target sites.


Asunto(s)
Tratamiento Farmacológico de COVID-19 , Proteínas Intrínsecamente Desordenadas , Descubrimiento de Drogas , Humanos , Proteínas Intrínsecamente Desordenadas/química , Proteínas Intrínsecamente Desordenadas/genética , Proteínas Intrínsecamente Desordenadas/metabolismo , Pandemias , SARS-CoV-2
11.
ACS Nano ; 16(11): 17802-17846, 2022 11 22.
Artículo en Inglés | MEDLINE | ID: mdl-36354238

RESUMEN

Exosomes are a subgroup of nanosized extracellular vesicles enclosed by a lipid bilayer membrane and secreted by most eukaryotic cells. They represent a route of intercellular communication and participate in a wide variety of physiological and pathological processes. The biological roles of exosomes rely on their bioactive cargos, including proteins, nucleic acids, and lipids, which are delivered to target cells. Their distinctive properties─innate stability, low immunogenicity, biocompatibility, and good biomembrane penetration capacity─allow them to function as superior natural nanocarriers for efficient drug delivery. Another notably favorable clinical application of exosomes is in diagnostics. They hold various biomolecules from host cells, which are indicative of pathophysiological conditions; therefore, they are considered vital for biomarker discovery in clinical diagnostics. Here, we use data from the CAS Content Collection and provide a landscape overview of the current state and delineate trends in research advancement on exosome applications in therapeutics and diagnostics across time, geography, composition, cargo loading, and development pipelines. We discuss exosome composition and pathway, from their biogenesis and secretion from host cells to recipient cell uptake. We assess methods for exosome isolation and purification, their clinical applications in therapy and diagnostics, their development pipelines, the exploration goals of the companies, the assortment of diseases they aim to treat, development stages of their research, and publication trends. We hope this review will be useful for understanding the current knowledge in the field of medical applications of exosomes, in an effort to further solve the remaining challenges in fulfilling their potential.


Asunto(s)
Exosomas , Nanopartículas , Sistemas de Liberación de Medicamentos/métodos , Liposomas/metabolismo , Exosomas/metabolismo
12.
J Med Chem ; 65(10): 6975-7015, 2022 05 26.
Artículo en Inglés | MEDLINE | ID: mdl-35533054

RESUMEN

In the past decade, there has been a shift in research, clinical development, and commercial activity to exploit the many physiological roles of RNA for use in medicine. With the rapid success in the development of lipid-RNA nanoparticles for mRNA vaccines against COVID-19 and with several approved RNA-based drugs, RNA has catapulted to the forefront of drug research. With diverse functions beyond the role of mRNA in producing antigens or therapeutic proteins, many classes of RNA serve regulatory roles in cells and tissues. These RNAs have potential as new therapeutics, with RNA itself serving as either a drug or a target. Here, based on the CAS Content Collection, we provide a landscape view of the current state and outline trends in RNA research in medicine across time, geography, therapeutic pipelines, chemical modifications, and delivery mechanisms.


Asunto(s)
Tratamiento Farmacológico de COVID-19 , Vacunas contra la COVID-19 , Humanos , ARN , ARN Mensajero/metabolismo , SARS-CoV-2
13.
ACS Nano ; 15(11): 16982-17015, 2021 11 23.
Artículo en Inglés | MEDLINE | ID: mdl-34181394

RESUMEN

Lipid nanoparticles (LNPs) have emerged across the pharmaceutical industry as promising vehicles to deliver a variety of therapeutics. Currently in the spotlight as vital components of the COVID-19 mRNA vaccines, LNPs play a key role in effectively protecting and transporting mRNA to cells. Liposomes, an early version of LNPs, are a versatile nanomedicine delivery platform. A number of liposomal drugs have been approved and applied to medical practice. Subsequent generations of lipid nanocarriers, such as solid lipid nanoparticles, nanostructured lipid carriers, and cationic lipid-nucleic acid complexes, exhibit more complex architectures and enhanced physical stabilities. With their ability to encapsulate and deliver therapeutics to specific locations within the body and to release their contents at a desired time, LNPs provide a valuable platform for treatment of a variety of diseases. Here, we present a landscape of LNP-related scientific publications, including patents and journal articles, based on analysis of the CAS Content Collection, the largest human-curated collection of published scientific knowledge. Rising trends are identified, such as nanostructured lipid carriers and solid lipid nanoparticles becoming the preferred platforms for numerous formulations. Recent advancements in LNP formulations as drug delivery platforms, such as antitumor and nucleic acid therapeutics and vaccine delivery systems, are discussed. Challenges and growth opportunities are also evaluated in other areas, such as medical imaging, cosmetics, nutrition, and agrochemicals. This report is intended to serve as a useful resource for those interested in LNP nanotechnologies, their applications, and the global research effort for their development.


Asunto(s)
COVID-19 , Nanopartículas , Humanos , Liposomas , ARN Mensajero , Lípidos/química , COVID-19/prevención & control , Nanopartículas/química , ARN Interferente Pequeño , Vacunas de ARNm
14.
ACS Cent Sci ; 7(4): 512-533, 2021 Apr 28.
Artículo en Inglés | MEDLINE | ID: mdl-34056083

RESUMEN

This report examines various vaccine platforms including inactivated vaccines, protein-based vaccines, viral vector vaccines, and nucleic acid (DNA or mRNA) vaccines, and their ways of producing immunogens in cells.

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