Current Medicinal Chemistry - Volume 27, Issue 21, 2020

Glycosaminoglycans (GAGs) are very complex, natural anionic polysaccharides. They are polymers of repeating disaccharide units of uronic acid and hexosamine residues. Owing to their template-free, spatiotemporally-controlled, and enzyme-mediated biosyntheses, GAGs possess enormous polydispersity, heterogeneity, and structural diversity which often translate into multiple biological roles. It is well documented that GAGs contribute to physiological and pathological processes by binding to proteins including serine proteases, serpins, chemokines, growth factors, and microbial proteins. Despite advances in the GAG field, the GAG-protein interface remains largely unexploited by drug discovery programs. Thus, Non-Saccharide Glycosaminoglycan Mimetics (NSGMs) have been rationally developed as a novel class of sulfated molecules that modulate GAG-protein interface to promote various biological outcomes of substantial benefit to human health. In this review, we describe the chemical, biochemical, and pharmacological aspects of recently reported NSGMs and highlight their therapeutic potentials as structurally and mechanistically novel anti-coagulants, anti-cancer agents, anti-emphysema agents, and anti-viral agents. We also describe the challenges that complicate their advancement and describe ongoing efforts to overcome these challenges with the aim of advancing the novel platform of NSGMs to clinical use.

The development of new therapeutic applications for adult and embryonic stem cells has dominated regenerative medicine and tissue engineering for several decades. However, since 2006, induced Pluripotent Stem Cells (iPSCs) have taken center stage in the field, as they promised to overcome several limitations of the other stem cell types. Nonetheless, other promising approaches for adult cell reprogramming have been attempted over the years, even before the generation of iPSCs. In particular, two years before the discovery of iPSCs, the possibility of synthesizing libraries of large organic compounds, as well as the development of high-throughput screenings to quickly test their biological activity, enabled the identification of a 2,6-disubstituted purine, named reversine, which was shown to be able to reprogram adult cells to a progenitor-like state. Since its discovery, the effect of reversine has been confirmed on different cell types, and several studies on its mechanism of action have revealed its central role in inhibitory activity on several kinases implicated in cell cycle regulation and cytokinesis. These key features, together with its chemical nature, suggested a possible use of the molecule as an anti-cancer drug. Remarkably, reversine exhibited potent cytotoxic activity against several tumor cell lines in vitro and a significant effect in decreasing tumor progression and metastatization in vivo. Thus, 15 years since its discovery, this review aims at critically summarizing the current knowledge to clarify the dual role of reversine as a dedifferentiating agent and anti-cancer drug.

Locoregional drug delivery is a novel approach for the effective delivery of anti-cancer agents as it exposes the tumors to high concentration of drugs. In situ gelling systems have fetched paramount attention in the field of localized cancer chemotherapy due to their targeted delivery, ease of preparation, prolonged or sustained drug release and improved patient compliance. Numerous polymers have been investigated for their properties like swelling along with biodegradation, drug release and physicochemical properties for successful targeting of the drugs at the site of implantation. The polymers such as chitosan, Hyaluronic Acid (HA), poloxamer, Poly Glycolic Lactic Acid (PGLA) and Poly Lactic Acid (PLA) tend to form in situ hydrogels and have been exploited to develop localized delivery vehicles. These formulations are administered in the solution form and on exposure to physiological environment such as temperature, pH or ionic composition they undergo phase conversion into a hydrogel drug depot. The use of in situ gelling approach has provided prospects to increase overall survival and life quality of cancer patient by enhancing the bioavailability of drug to the site of tumor by minimizing the exposure to normal cells and alleviating systemic side effects. Because of its favorable safety profile and clinical benefits, United States Food and Drug Administration (U.S. FDA) has approved polymer based in situ systems for prolonged locoregional activity. This article discusses the rationale for developing in situ systems for targeted delivery of anti-cancer agents with special emphasis on types of polymers used to formulate the in situ system. In situ formulations for locoregional anti-cancer drug delivery that are marketed and are under clinical trials have also been discussed in detail in this article.

In mammals, catabolism of the heme group is indispensable for life. Heme is first cleaved by the enzyme Heme Oxygenase (HO) to the linear tetrapyrrole Biliverdin IXα (BV), and BV is then converted into bilirubin by Biliverdin Reductase (BVR). HO utilizes three Oxygen molecules (O2) and seven electrons supplied by NADPH-cytochrome P450 oxidoreductase (CPR) to open the heme ring and BVR reduces BV through the use of NAD(P)H. Structural studies of HOs, including substrate-bound, reaction intermediate-bound, and several specific inhibitor-bound forms, reveal details explaining substrate binding to HO and mechanisms underlying-specific HO reaction progression. Cryo-trapped structures and a time-resolved spectroscopic study examining photolysis of the bond between the distal ligand and heme iron demonstrate how CO, produced during the HO reaction, dissociates from the reaction site with a corresponding conformational change in HO. The complex structure containing HO and CPR provides details of how electrons are transferred to the heme-HO complex. Although the tertiary structure of BVR and its complex with NAD+ was determined more than 10 years ago, the catalytic residues and the reaction mechanism of BVR remain unknown. A recent crystallographic study examining cyanobacterial BVR in complex with NADP+ and substrate BV provided some clarification regarding these issues. Two BV molecules are bound to BVR in a stacked manner, and one BV may assist in the reductive catalysis of the other BV. In this review, recent advances illustrated by biochemical, spectroscopic, and crystallographic studies detailing the chemistry underlying the molecular mechanism of HO and BVR reactions are presented.

The discovery of new biomarkers associated with cancer, neurological and cardiovascular diseases is necessary, since these are common, recurrent diseases considered as leading causes of death in the human population. Molecular signatures of these disorders that can be identified at the outset of their pathogenesis leading to prompt and targeted treatment may increase patient survival. Cancer is a heterogeneous disease that can be expressed differently among individuals; in addition, treatments may have a differentiated approach according to the type of malignant neoplasm. Thus, these neoplastic cells can synthesize and release specific molecules depending on the site where carcinogenesis begins. Moreover, life expectancy is increasing especially in developed countries, however, cases of neurodegenerative diseases have grown in the older members of the population. Commonly, some neurological disorders, which can occur physiologically by the process of senescence, are confused with Alzheimer's Disease (AD). In addition, cardiovascular diseases are the main cause of death in the world; studies capable of identifying, through molecular probes, the beginning of development of an atherosclerotic process can lead to early treatment to avoid an acute myocardial infarction. Accuracy in the detection of these biomarkers can be obtained through biosensors whose design has been increasingly studied to elaborate inexpensive sensory platforms capable of precise detection, even at low concentrations, of the molecule to be measured. The aim of this review is to address biomarkers to be used in diagnoses instead of invasive exams; biosensors for the specific and sensitive detection of these biological markers are also investigated.

Atherosclerosis is the leading inducement of cardiovascular diseases, which ranks the first cause of global deaths. It is an arterial disease associated with dyslipidemia and changes in the composition of the vascular wall. Besides invasive surgical strategy, the current conservative clinical treatment for atherosclerosis falls into two categories, lipid regulating-based therapy and antiinflammatory therapy. However, the existing strategies based on conventional drug delivery systems have shown limited efficacy against disease development and plenty of side effects. Nanomedicine has great potential in the development of targeted therapy, controlled drug delivery and release, the design of novel specific drugs and diagnostic modalities, and biocompatible scaffolds with multifunctional characteristics, which has led to an evolution in the diagnosis and treatment of atherosclerosis. This paper will focus on the latest nanomedicine strategies for atherosclerosis diagnosis and treatment as well as discussing the potential therapeutic targets during atherosclerosis progress, which could form the basis of development of novel nanoplatform against atherosclerosis.

Gluten triggers Celiac Disease (CD) and type I diabetes in genetically predisposed population of human leukocyte antigen DQ2/DQ8+ and associates with disorders such as schizophrenia and autism. Application of a strict gluten-free diet is the only well-established treatment for patients with CD, whereas the treatment for patients with celiac type I diabetes may be depend on the timing and frequency of the diet. The application of a gluten-free diet in patients with CD may contribute to the development of metabolic syndrome and nonalcoholic fatty liver disease and may also lead to a high glycemic index, low fiber diet and micronutrient deficiencies. The alteration of copper bioavailability (deficient, excess or aberrant coordination) may contribute to the onset and progress of related pathologies. Therefore, nutrient intake of patients on a gluten-free diet should be the focus of future researches. Other gluten-based therapies have been rising with interest such as enzymatic pretreatment of gluten, oral enzyme supplements to digest dietary gluten, gluten removal by breeding wheat varieties with reduced or deleted gluten toxicity, the development of polymeric binders to suppress gluten induced pathology.

Obesity, associated with a series of complications such as diabetes, hypertension, and heart disease, is a great threat to human health and leads to increased morbidity and mortality. Despite the presence of anti-obesity agents on the market, the application of these drugs is limited because of their typical side effects. More effective and safe weight-loss drugs are being pursued by many researchers, correspondingly, growing small molecules and natural products with anti-obesity effects have been identified and the molecular mechanisms underlying the action of the novel and known compounds have at least partially been revealed. Therefore, the field does witness great progress year by year. In this review, we intend to provide a comprehensive and updated view on the known and novel compounds which possess anti-obesity effects and further classify them according to the molecular mechanisms of their actions in regulating the major anti-obesity pathways.