Targeting the tumor microenvironment in colorectal peritoneal metastases

Peritoneal metastasis (PM) occurs in approximately one in four colorectal cancer (CRC) patients. The pathophysiology of colorectal PM remains poorly characterized. Also, the efficacy of current treatment modalities, including surgery and intraperitoneal (IP) delivery of chemotherapy, is limited. Increasingly, therefore, efforts are being developed to unravel the PM cascade and at understanding the PM-associated tumor microenvironment (TME) and peritoneal ecosystem as potential therapeutic targets. Here, we review recent insights in the structure and components of the TME in colorectal PM, and discuss how these may translate into novel therapeutic approaches aimed at re-engineering the metastasis-promoting activity of the stroma

Trends in the design and use of elastin-like recombinamers as biomaterials

Producción CientíficaElastin-like recombinamers (ELRs), which derive from one of the repetitive domains found in natural elastin, have been intensively studied in the last few years from several points of view. In this mini review, we discuss all the recent works related to the investigation of ELRs, starting with those that define these polypeptides as model intrinsically disordered proteins or regions (IDPs or IDRs) and its relevance for some biomedical applications. Furthermore, we summarize the current knowledge on the development of drug, vaccine and gene delivery systems based on ELRs, while also emphasizing the use of ELR-based hydrogels in tissue engineering and regenerative medicine (TERM). Finally, we show different studies that explore applications in other fields, and several examples that describe biomaterial blends in which ELRs have a key role. This review aims to give an overview of the recent advances regarding ELRs and to encourage further investigation of their properties and applications.Comisión Europea (project NMP-2014-646075)Ministerio de Economía, Industria y Competitividad (projects PCIN-2015-010 / MAT2016-78903-R / BES-2014-069763)Junta de Castilla y León (project VA317P18

Computational approaches in antibody-drug conjugate optimization for targeted cancer therapy

WOS: 000444683500007PubMed ID: 30068276Cancer has become one of the main leading causes of morbidity and mortality worldwide. One of the critical drawbacks of current cancer therapeutics has been the lack of the target-selectivity, as these drugs should have an effect exclusively on cancer cells while not perturbing healthy ones. In addition, their mechanism of action should be sufficiently fast to avoid the invasion of neighbouring healthy tissues by cancer cells. The use of conventional chemotherapeutic agents and other traditional therapies, such as surgery and radiotherapy, leads to off-target interactions with serious side effects. In this respect, recently developed target-selective Antibody-Drug Conjugates (ADCs) are more effective than traditional therapies, presumably due to their modular structures that combine many chemical properties simultaneously. In particular, ADCs are made up of three different units: a highly selective Monoclonal antibody (Mab) which is developed against a tumour-associated antigen, the payload (cytotoxic agent), and the linker. The latter should be stable in circulation while allowing the release of the cytotoxic agent in target cells. The modular nature of these drugs provides a platform to manipulate and improve selectivity and the toxicity of these molecules independently from each other. This in turn leads to generation of second-and third-generation ADCs, which have been more effective than the previous ones in terms of either selectivity or toxicity or both. Development of ADCs with improved efficacy requires knowledge at the atomic level regarding the structure and dynamics of the molecule. As such, we reviewed all the most recent computational methods used to attain all-atom description of the structure, energetics and dynamics of these systems. In particular, this includes homology modelling, molecular docking and refinement, atomistic and coarse-grained molecular dynamics simulations, principal component and cross-correlation analysis. The full characterization of the structure-activity relationship devoted to ADCs is critical for antibody-drug conjugate research and development.Fundacao para a Ciencia e a Tecnologia (FCT) Investigator programme [IF/00578/2014]; European Social Fund; Programa Operacional Potencial Humano; Marie Sklodowska-Curie Individual Fellowship MSCA-IF-2015 [MEMBRANEPROT 659826]; European Regional Development Fund (ERDF), through the Centro 2020 Regional Operational Programme [CENTRO-01-0145-FEDER-000008]; European Regional Development Fund (ERDF), COMPETE 2020 - Operational Programme for Competitiveness and Internationalisation; Portuguese national funds via FCT [POCI-01-0145-FEDER-007440]; FCT [FCT-SFRH/BPD/97650/2013]; Fundacao para a Ciencia e Tecnologia (FCT), Portugal [UID/Multi/04349/2013]Irina S. Moreira acknowledges support by the Fundacao para a Ciencia e a Tecnologia (FCT) Investigator programme - IF/00578/2014 (co-financed by European Social Fund and Programa Operacional Potencial Humano), and a Marie Sklodowska-Curie Individual Fellowship MSCA-IF-2015 [MEMBRANEPROT 659826]. This work was also financed by the European Regional Development Fund (ERDF), through the Centro 2020 Regional Operational Programme under project CENTRO-01-0145-FEDER-000008: Brain-Health 2020, and through the COMPETE 2020 - Operational Programme for Competitiveness and Internationalisation and Portuguese national funds via FCT, under project POCI-01-0145-FEDER-007440. Rita Melo acknowledges support from the FCT (FCT-SFRH/BPD/97650/2013). This work has been partially supported by the Fundacao para a Ciencia e Tecnologia (FCT), Portugal, through the UID/Multi/04349/2013 project in Centre for Nuclear Sciences and Technologies (C2TN)

The inhibition of Stat5 by a peptide aptamer ligand specific for the DNA binding domain prevents target gene transactivation and the growth of breast and prostate tumor cells

The signal transducer and activator of transcription Stat5 is transiently activated by growth factor and cytokine signals in normal cells, but its persistent activation has been observed in a wide range of human tumors. Aberrant Stat5 activity was initially observed in leukemias, but subsequently also found in carcinomas. We investigated the importance of Stat5 in human tumor cell lines. shRNA mediated downregulation of Stat5 revealed the dependence of prostate and breast cancer cells on the expression of this transcription factor. We extended these inhibition studies and derived a peptide aptamer (PA) ligand, which directly interacts with the DNA-binding domain of Stat5 in a yeast-two-hybrid screen. The Stat5 specific PA sequence is embedded in a thioredoxin (hTRX) scaffold protein. The resulting recombinant protein S5-DBD-PA was expressed in bacteria, purified and introduced into tumor cells by protein transduction. Alternatively, S5-DBD-PA was expressed in the tumor cells after infection with a S5-DBD-PA encoding gene transfer vector. Both strategies impaired the DNA-binding ability of Stat5, suppressed Stat5 dependent transactivation and caused its intracellular degradation. Our experiments describe a peptide based inhibitor of Stat5 protein activity which can serve as a lead for the development of a clinically useful compound for cancer treatment

Developing Regenerative Treatments for Developmental Defects, Injuries, and Diseases Using Extracellular Matrix Collagen-Targeting Peptides.

Collagen is the most widespread extracellular matrix (ECM) protein in the body and is important in maintaining the functionality of organs and tissues. Studies have explored interventions using collagen-targeting tissue engineered techniques, using collagen hybridizing or collagen binding peptides, to target or treat dysregulated or injured collagen in developmental defects, injuries, and diseases. Researchers have used collagen-targeting peptides to deliver growth factors, drugs, and genetic materials, to develop bioactive surfaces, and to detect the distribution and status of collagen. All of these approaches have been used for various regenerative medicine applications, including neovascularization, wound healing, and tissue regeneration. In this review, we describe in depth the collagen-targeting approaches for regenerative therapeutics and compare the benefits of using the different molecules for various present and future applications

A Human-Derived Monoclonal Antibody Targeting Extracellular Connexin Domain Selectively Modulates Hemichannel Function

Connexin hemichannels, which are plasma membrane hexameric channels (connexons) composed of connexin protein protomers, have been implicated in a host of physiological processes and pathological conditions. A number of single point pathological mutations impart a "leaky" character to the affected hemichannels, i.e., make them more active or hyperactive, suggesting that normal physiological condition could be recovered using selective hemichannel inhibitors. Recently, a human-derived monoclonal antibody named abEC1.1 has been shown to inhibit both wild type and hyperactive hemichannels composed of human (h) connexin 26 (hCx26) subunits. The aims of this work were (1) to characterize further the ability of abEC1.1 to selectively modulate connexin hemichannel function and (2) to assess its in vitro stability in view of future translational applications. In silico analysis of abEC1.1 interaction with the hCx26 hemichannel identified critically important extracellular domain amino acids that are conserved in connexin 30 (hCx30) and connexin 32 (hCx32). Patch clamp experiments performed in HeLa DH cells confirmed the inhibition efficiency of abEC1.1 was comparable for hCx26, hCx30 and hCx32 hemichannels. Of note, even a single amino acid difference in the putative binding region reduced drastically the inhibitory effects of the antibody on all the other tested hemichannels, namely hCx30.2/31.3, hCx30.3, hCx31, hCx31.1, hCx37, hCx43 and hCx45. Plasma membrane channels composed of pannexin 1 were not affected by abEC1.1. Finally, size exclusion chromatography assays showed the antibody does not aggregate appreciably in vitro. Altogether, these results indicate abEC1.1 is a promising tool for further translational studies

Innovative Therapeutic Strategies in Alzheimer’s Disease:A Synergistic Approach to Neurodegenerative Disorders

Alzheimer’s disease (AD) remains a significant challenge in the field of neurodegenerative disorders, even nearly a century after its discovery, due to the elusive nature of its causes. The development of drugs that target multiple aspects of the disease has emerged as a promising strategy to address the complexities of AD and related conditions. The immune system’s role, particularly in AD, has gained considerable interest, with nanobodies representing a new frontier in biomedical research. Advances in targeting antibodies against amyloid-β (Aβ) and using messenger RNA for genetic translation have revolutionized the production of antibodies and drug development, opening new possibilities for treatment. Despite these advancements, conventional therapies for AD, such as Cognex, Exelon, Razadyne, and Aricept, often have limited long-term effectiveness, underscoring the need for innovative solutions. This necessity has led to the incorporation advanced technologies like artificial intelligence and machine learning into the drug discovery process for neurodegenerative diseases. These technologies help identify therapeutic targets and optimize lead compounds, offering a more effective approach to addressing the challenges of AD and similar conditions

The year in review: progress in brain barriers and brain fluid research in 2018

Abstract This editorial focuses on the progress made in brain barrier and brain fluid research in 2018. It highlights some recent advances in knowledge and techniques, as well as prevalent themes and controversies. Areas covered include: modeling, the brain endothelium, the neurovascular unit, the blood–CSF barrier and CSF, drug delivery, fluid movement within the brain, the impact of disease states, and heterogeneity.https://deepblue.lib.umich.edu/bitstream/2027.42/147737/1/12987_2019_Article_124.pd

Overview of P-glycoprotein inhibitors: a rational outlook

Glicoproteína-p (P-gp), uma glicoproteína de transmembrana permeável, é um membro da superfamília (ABC) de cassete de gene de ligação de ATP que funciona especificamente como um carreador mediado pelo transportador de efluxo ativo primário. É amplamente distribuído por todo o corpo e apresenta uma gama diversificada de substratos. Diversos agentes terapêuticos vitais são substratos para P-gp e sua biodisponibilidade é reduzida ou a resistência é induzida devido ao efluxo de proteínas. Portanto, os inibidores da P-gp foram explorados para a superação da resistência a múltiplas drogas e problemas de biodisponibilidade deficiente dos substratos terapêuticos da P-gp. A sensibilidade das moléculas da droga à P-gp e vice-versa, pode ser estabelecida por vários modelos experimentais in silico, in vitro e in vivo. Desde a descoberta da P-gp, diversas pesquisas identificaram várias estruturas químicas como inibidores da P-gp. O objetivo deste presente estudo foi o de enfatizar a descoberta e desenvolvimento de inibidores mais novos, inertes, atóxicos e mais eficazes, visando especificamente os da P-gp, como aqueles entre os extratos vegetais, excipientes e formulações farmacêuticas, e outras moléculas racionais de droga. As aplicações do conhecimento de biologia celular e molecular, bancos de dados estruturais in silico, estudos de modelagem molecular e análises da relação quantitativa estrutura-atividade (QSAR) no desenvolvimento de novos inibidores racionais da P-gp também foram mencionados.P-glycoprotein (P-gp), a transmembrane permeability glycoprotein, is a member of ATP binding cassette (ABC) super family that functions specifically as a carrier mediated primary active efflux transporter. It is widely distributed throughout the body and has a diverse range of substrates. Several vital therapeutic agents are substrates to P-gp and their bioavailability is lowered or a resistance is induced because of the protein efflux. Hence P-gp inhibitors were explored for overcoming multidrug resistance and poor bioavailability problems of the therapeutic P-gp substrates. The sensitivity of drug moieties to P-gp and vice versa can be established by various experimental models in silico, in vitro and in vivo. Ever since the discovery of P-gp, the research plethora identified several chemical structures as P-gp inhibitors. The aim of this review was to emphasize on the discovery and development of newer, inert, non-toxic, and more efficient, specifically targeting P-gp inhibitors, like those among the natural herb extracts, pharmaceutical excipients and formulations, and other rational drug moieties. The applications of cellular and molecular biology knowledge, in silico designed structural databases, molecular modeling studies and quantitative structure-activity relationship (QSAR) analyses in the development of novel rational P-gp inhibitors have also been mentioned