Current Medicinal Chemistry - Volume 27, Issue 22, 2020

The plasma membrane of eukaryotic cells defines the boundary to the extracellular environment and, thus provides essential protection from the surroundings. Consequently, disruptions to the cell membrane triggered by excessive mechanical or biochemical stresses pose fatal threats to cells, which they need to cope with to survive. Eukaryotic cells cope with these threats by activating their plasma membrane repair system, which is shared by other cellular functions, and includes mechanisms to remove damaged membrane by internalization (endocytosis), shedding, reorganization of cytoskeleton and membrane fusion events to reseal the membrane. Members of the annexin protein family, which are characterized by their Ca2+-dependent binding to anionic phospholipids, are important regulators of plasma membrane repair. Recent studies based on cellular and biophysical membrane models show that they have more distinct functions in the repair response than previously assumed by regulating membrane curvature and excision of damaged membrane. In cells, plasma membrane injury and flux of Ca2+ ions into the cytoplasm trigger recruitment of annexins including annexin A4 and A6 to the membrane wound edges. Here, they induce curvature and constriction force, which help pull the wound edges together for eventual fusion. Cancer cells are dependent on efficient plasma membrane repair to counteract frequent stress-induced membrane injuries, which opens novel avenues to target cancer cells through their membrane repair system. Here, we discuss mechanisms of single cell wound healing implicating annexin proteins and membrane curvature.

Omic-technologies (genomics, transcriptomics, proteomics and metabolomics) have become more important in current medical science. Among them, it is metabolomics that most accurately reflects the minor changes in body functioning, as it focuses on metabolome – the group of the metabolism products, both intermediate and end. Therefore, metabolomics is actively engaged in fundamental and clinical studies and search for potential biomarkers. The biomarker could be used in diagnostics, management and stratification of the patients, as well as in prognosing the outcomes. The good example is gynecology, since many gynecological diseases lack effective biomarkers. In the current review, we aimed to summarize the results of the studies, devoted to the search of potential metabolomic biomarkers for the most common gynecological diseases.

Colloidal carriers diverge depending on their composition, ability to incorporate drugs and applicability, but the common feature is the small average particle size. Among the carriers with the potential nanostructured drug delivery application there are SLN and NLC. These nanostructured systems consist of complex lipids and highly purified mixtures of glycerides having varying particle size. Also, these systems have shown physical stability, protection capacity of unstable drugs, release control ability, excellent tolerability, possibility of vectorization, and no reported production problems related to large-scale. Several production procedures can be applied to achieve high association efficiency between the bioactive and the carrier, depending on the physicochemical properties of both, as well as on the production procedure applied. The whole set of unique advantages such as enhanced drug loading capacity, prevention of drug expulsion, leads to more flexibility for modulation of drug release and makes Lipid-based nanocarriers (LNCs) versatile delivery system for various routes of administration. The route of administration has a significant impact on the therapeutic outcome of a drug. Thus, the non-invasive routes, which were of minor importance as parts of drug delivery in the past, have assumed added importance drugs, proteins, peptides and biopharmaceuticals drug delivery and these include nasal, buccal, vaginal and transdermal routes. The objective of this paper is to present the state of the art concerning the application of the lipid nanocarriers designated for non-invasive routes of administration. In this manner, this review presents an innovative technological platform to develop nanostructured delivery systems with great versatility of application in non-invasive routes of administration and targeting drug release.

Accumulating evidences indicated that obesity and metabolic syndrome were independent risk factors for the development and progression of kidney diseases. Apart from inflammation, lipotoxicity, and hemodynamic factors, adipokines have been proposed to play crucial roles in the relationship between kidney diseases and metabolic disorders. As one of the key adipokines, fatty acid binding protein 4 (FABP4), which is mainly expressed in adipocytes and macrophages, has recently been shown to be associated with renal dysfunction and kidney damage. Both clinical and experimental studies have proposed circulating FABP4 as a novel predictor for renal injuries, and it might also be a predictor for cardiovascular events in patients with end stage renal disease (ESRD). FABP4 has also been detected in the glomerular cells and epithelial tubular cells in mouse and human kidneys, and the expression of FABP4 in these cells has been involved in the pathogenesis of kidney diseases. In addition, experimental studies suggested that inhibition of FABP4 had protective effects on renal damage. Here, we reviewed current knowledge regarding the role of FABP4 in pathophysiological insights as well as its potential function as a predictor and therapeutic target for kidney diseases.

Motivated by the accomplishment of carbon nanotubes (CNTs), graphene and graphene oxide (GO) has been widely investigated in the previous studies as an innovative medication nanocarrier for the loading of a variety of therapeutics as well as anti-cancer medications, poor dissolvable medications, antibiotics, antibodies, peptides, DNA, RNA and genes. Graphene provides the ultra-high drug-loading efficiency due to the wide surface area. Graphene and graphene oxide have been widely investigated for biomedical applications due to their exceptional qualities: twodimensional planar structure, wide surface area, chemical and mechanical constancy, sublime conductivity and excellent biocompatibility. Due to these unique qualities, GO applications provide advanced drug transports frameworks and transports of a broad range of therapeutics. In this review, we discussed the latest advances and improvements in the uses of graphene and GO for drug transport and nanomedicine. Initially, we have described what is graphene and graphene oxide. After that, we discussed the qualities of GO as a drug carrier, utilization of GO in drug transport applications, targeted drug transport, transport of anticancer medications, chemical control medicine releasee, co-transport of different medications, comparison of GO with CNTs, nano-graphene for drug transport and at last, we have discussed the graphene toxicity. Finally, we draw a conclusion of current expansion and the potential outlook for the future.

Serine proteases play critical roles in many physiological and pathological processes, and are proven diagnostic and therapeutic targets in a number of clinical indications. Suppression of the aberrant proteolytic activities of these proteases has been clinically used for the treatments of relevant diseases. Polypeptides with 10-20 residues are of great interests as medicinal modulators of serine proteases, because these peptides demonstrate the characteristics of both small molecule drugs and macromolecular drugs. In this review, we summarized the recent development of peptide-based inhibitors against serine proteases with potent inhibitory and high specificity comparable to monoclonal antibodies. In addition, we also discussed the strategies of enhancing plasma half-life and bioavailability of peptides in vivo, which is the main hurdle that limits the clinical translation of peptide-based drugs. This review advocates new avenue for the development of effective serine protease inhibitors and highlights the prospect of the medicinal use of these inhibitors.

Cancer is a leading cause of death worldwide. It initiates when cell cycle regulatory genes lose their function either by environmental and/or by internal factors. Tumor suppressor protein p53, known as “Guardian of genome”, plays a central role in maintaining genomic stability of the cell. Mutation of TP53 is documented in more than 50% of human cancers, usually by overexpression of negative regulator protein MDM2. Hence, reactivation of p53 by blocking the protein-protein interaction between the murine double minute 2 (MDM2) and the tumor suppressor protein p53 has become the most promising therapeutic strategy in oncology. Several classes of small molecules have been identified as potent, selective and efficient p53-MDM2 inhibitors. Herein, we review the druggability of p53-MDM2 inhibitors and their optimization approaches as well as clinical candidates categorized by scaffold type.

Ruthenium complexes have stood out by several mononuclear complexes which have entered into clinical trials, such as imidazolium [trans-RuCl4(1H-imidazole)(DMSO-S)] (NAMI-A) and ([Ru(II)(4,4'-dimethyl-2,2'-bipyridine)2-(2(2'-,2":5",2"'-terthiophene)-imidazo[4,5-f] [1,10]phenanthroline)] 2+) (TLD-1433), opening a new avenue for developing promising ruthenium-based anticancer drugs alternative to Cisplatin. Polynuclear ruthenium complexes were reported to exhibit synergistic and/or complementary effects: the enhanced DNA structural recognition and DNA binding as well as in vitro anticancer activities. This review overviews some representative polynuclear ruthenium complexes acting as DNA structural probes, DNA binders and in vitro anticancer agents, which were developed during last decades. These complexes are reviewed according to two main categories of homo-polynuclear and hetero-polynuclear complexes, each of which is further clarified into the metal centers linked by rigid and flexible bridging ligands. The perspective, challenges and future efforts for investigations into these exciting complexes are pointed out or suggested.

Osteoarthritis (OA) is an age-related degenerative disease, which is characterized by chronic joint pain, inflammation and the damage of joint cartilage. At present, steroidal drugs and nonsteroidal anti-inflammatory drugs (NSAIDS), selective cyclooxygenase-2 (COX-2) inhibitors, are the first-line drugs for the treatment of OA. However, these drugs could lead to some cardiovascular side effects. Therefore, it is urgent to develop novel agents for the treatment of OA. Matrix metalloproteinase-13 (MMP-13), an important member of matrix metalloproteinases (MMPs) family, plays a vital role by degrading type II collagen in articular cartilage and bone in OA. It is noted that MMP-13 is specially expressed in the OA patients, and not in normal adults. In addition, broadspectrum MMP inhibitors could result in some painful and joint-stiffening side effects, called musculoskeletal syndrome (MSS) in the clinical trials. Thus, developing selective MMP-13 inhibitors is a potential strategy for the therapy of OA. In this review, we summarize the recent progress of selective MMP-13 inhibitors including two subfamilies, namely zinc-binding and non-zinc-binding selective MMP-13 inhibitors.