Current Medicinal Chemistry - Volume 24, Issue 30, 2017

Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) are some of the most widely prescribed or dispensed over the counter analgesics and antipyretics that act by inhibiting prostaglandins and thromboxane synthesis. After the identification of a second isoform of COX, the pharmaceutical research focused on developing COX-2- selective drugs (COXIBs) considered as second generation NSAIDs that would retain the anti-inflammatory and analgesic activities of traditional NSAID without blunting the gastrointestinal cytoprotection sustained by COX1-derived products such as PGE2. However, while several clinical trials confirmed a gastrointestinal safer profile of COXIBs vs unselective COX inhibitors, increasing evidence for potential cardiovascular risk associated with COXIBs rapidly emerged. Today, there are no really safe NSAIDs to be used in chronic pain and anti-inflammatory treatments, as an adequate therapy associated with a minimal gastrointestinal damage and cardiovascular toxicity is yet to be developed. Objective: Here, we present evidences that combining the anti-aggregating and antiatherotrombotic activities of a thromboxane receptor antagonist with the antiinflammatory activity of a COXIB we could obtain a new multitarget drug providing protection against the harmful activities mediated by the COXIB component, yet exploiting its recognized therapeutic advantages as a gastrointestinal-safer anti-inflammatory drug. We also summarize recent progress achieved in this field of research and possible new strategies to obtain a new bivalent compound. Conclusion: This possible third-generation NSAID with a safer pharmacological profile, will have all the pharmacological characteristics for the long-term therapy of chronic disorders such as inflammatory diseases or selected forms of cancer.

Angiotensin converting enzyme (ACE) 2 is a homologue of ACE that catalyzes the conversion of Angiotensin (Ang) II into Ang1-7, which induces vasodilation, anti-fibrotic, anti-proliferative and anti-inflammatory effects. Given that ACE2 counterbalances the effects of Ang II, it has been proposed as a biomarker in kidney disease patients. Circulating ACE2 has been studied in human and experimental studies under physiological and pathological conditions and different techniques have been assessed to determine its enzymatic activity. In patients with cardiovascular (CV) disease circulating ACE2 has been shown to be increased. In addition, hypertensive and diabetic patients have also shown higher circulating ACE2 activities. A study in type 1 diabetes patients found a negative association between circulating ACE2 and estimated glomerular filtration rate in male and female patients. Recently, it has been demonstrated that circulating ACE2 is increased in male patients with chronic kidney disease (CKD) and that it is independently associated with other classical CV risk factors, such as advanced age and diabetes. Furthermore, circulating ACE2 has been shown to be associated with silent atherosclerosis and CV outcomes in CKD patients. In diabetic nephropathy, experimental studies have demonstrated an increase in circulating ACE2 activity both at early and late stages of the disease, as well as a direct association with increased urinary albumin excretion, suggesting that it may be increased as a renoprotective mechanism in these patients. In this paper we will review the measurement of circulating ACE2 and its role in kidney disease, as well as its potential role as a renal and CV biomarker.

Background: The multicomponent primary active ATP-binding cassette transporter Cdr1p in the structure of the pathogenic yeast Candida albicans is among the culprits of antifungal agent resistance reported in recent decades. So far, various potential novel inhibitors/ modulators of this protein have been purified, synthesized, and biologically tested, with results showing their ability to effectively reverse CaCdr1p-mediated drug resistance phenomenon. These compounds are of diverse origins, possess non-identical structural features and adopt different mechanisms of action. Method: A structured search of chemical features and mechanisms of studied modulators of CaCdr1p was carried out using both original research publications and review articles. The nature of possible inhibitory mechanisms against the pump was analyzed in relation to the structure and the activity of the transporter. A process of summarizing modulatory spectra of the listed compounds against 2 other efflux pumps of Candida albicans namely Cdr2p and Mdr1p was also conducted, during which selective inhibitors of Cdr1p were revealed. Results: In this article, 6 possible mechanisms with which a molecule can manifest their activity against the efflux pump are described, and a list of nearly 50 CaCdr1p modulators found in literatures along with their respective mechanism(s) (if already identified) is provided, summarizing the results obtained so far in the search of new inhibitors of the drug extrusion transporter that can enhance the potency of commonly used antifungal agents. A table of inhibitory spectra of the listed compounds against Cdr1p, Cdr2p and Mdr1p is also given, with several selective modulators of Cdr1p finally indicated. Conclusion: The findings of this review contribute to future studies regarding CaCdr1p and its modulators by summarizing the results obtained so far on this emerging issue of health sciences. Further research concerning novel compounds capable of inhibiting Cdr1p needs to be carried out in hopes of completing the lists provided in this article.

Snake venoms are natural sources of biologically active molecules that are able to act selectively and specifically on different cellular targets, modulating physiological functions. Thus, these mixtures, composed mainly of proteins and peptides, provide ample and challenging opportunities and a diversified molecular architecture to design and develop tools and agents of scientific and therapeutic interest. Among these components, peptides and small proteins play diverse roles in numerous physiological processes, exerting a wide range of pharmacological activities, such as antimicrobial, antihypertensive, analgesic, antitumor, analgesic, among others. The pharmaceutical and cosmetic industries have recognized the huge potential of these privileged frameworks and believe them to be a promising alternative to contemporary drugs. A number of natural or synthetic peptides from snake venoms have already found preclinical or clinical applications for the treatment of pain, hypertension, cardiovascular diseases and aging skin. A well-known example is captopril, whose natural peptide precursor was isolated from Bothrops jararaca snake venom, which is a peptide-based drug that inhibits the angiotensin-converting enzyme, producing an anti-hypertensive effect. The present review looks at the main peptides (natriuretic peptides, bradykinin-potentiating peptides and sarafotoxins) and low mass proteins (crotamine, disintegrins and three-Finger toxins) from snake venoms, as well as synthetic peptides inspired by them, describing their biochemical, structural and physiological features, as well as their applications as research tools and therapeutic agents.

Background: Acetylcholinesterase (AChE) is involved in the termination of impulse transmission by rapid hydrolysis of the neurotransmitter acetylcholine in numerous cholinergic pathways in the central and peripheral nervous systems. The enzyme inactivation leads to acetylcholine accumulation, hyperstimulation of nicotinic and muscarinic receptors, and disrupted neurotransmission. Hence, acetylcholinesterase inhibitors, interacting with the enzyme as their primary target, are applied as relevant drugs for different neurodegenerative diseases (such as Alzheimer's and Parkinson's) as well as toxins. At the same time, there are increasing evidence that in non-neuronal context, AChE is involved in the regulation of cell proliferation, differentiation, apoptosis and cell-cell interaction. An irregular expression of AChE has been found in different types of tumors, suggesting the involvement of AChE in the regulation of tumor development. Having all this in mind, there is a possibility that some AChE inhibitors could be used as anti-cancer agents. Objective: This contribution will discuss a broad range of possible application of different AChE inhibitors as drugs, from well-known anti-Alzheimer's disease drugs to their use in cancer treatment in future. Emphasis will be put on various known AChE inhibitors classes, whose application as drugs could be controversy, as well as on newly investigated natural products, which can also modulate AChE activity. Conclusion: It is not clear a patient treated for neurodegenerative condition prone to increased risk for some types of cancer and vice versa. This is necessary to keep in mind during rational drug design process for all therapies, which are based on AChE as a target molecule.

Background: Drug encapsulated nanoparticle has the potency to act as an effective antidote for various diseases. It is possible to enhance the bioavailability of drug encapsulated nanoparticle, whereby the yield is significantly higher compared to the standard formulation. The development with drug encapsulated nanoparticle has been improved drastically after demonstrating its capability of showing the enhanced thermophysical properties and stability of the drug. It is also utilized widely in cancer diagnoses, whereby the surface of the nanoparticle can be modified to enable the nanocarriers to reach the targeted location. Thus, the encapsulated nanoparticle can reveal neural stem cell differentiation due to the multifaceted nature and the biophysical cues to control the cell differentiation. Objective: In this overview, different advantages of the drug encapsulated nanoparticle for the downstream applications are narrated with its appealing characteristics. Conclusion: The application of the drug encapsulated nanoparticle is unrestricted as it can be customized to the specific target cell in the living system.