Current Medicinal Chemistry - Volume 20, Issue 31, 2013

A variety of peptides active in biological pathways have been identified e.g. receptor antagonists or inhibitors of protein–protein interactions and several peptide or peptide-derived compounds are on the drug market or in clinical trials. Through the rational design or the combinatorial preparation and High-throughput screening of arrays of compounds, peptides play a pivotal role for the rapid identification of ligands, but, despite these favorable properties, they often present poorer bioavailability and lower metabolic stability respect to traditional drugs. The process of conversion of a peptide in a small molecule provides the reduction of the peptide to the minimum active sequence (MAS) testing truncated peptides from the C- and N- termini alternatively. Then the influence of individual amino acid on the biological activity is determined by systematically replacing each residue in the peptide with specific amino acids. After structure–activity relationship (SAR) of each amino acid in the sequence has been assessed, the bioactive conformational flexibility is reduced by introducing constraints at various positions. These features are used for the design of a pharmacophore model in which functional groups crucial for activity are pre-positioned. Here we propose a panoramic review of the common principles for the conversion of peptides into small organic molecules and the most interesting findings in peptide-based leads of the last decades.

Epidemiological and family studies have provided evidence on the role of genetic factors in stroke, particularly in stroke occurring at young age. However, despite its impact, young stroke continues to be understudied. This article reviews the existing literature on the most investigated monogenic disorders (CADASIL, Fabry disease, MELAS, RVCL, COL4A1, Marfan and Ehlers-Danlos syndromes) causing stroke in young and a number of candidate genes associated with stroke occurring in patients younger than 50 years. Although our study failed in identifying strong and reliable associations between specific genes and young stroke, our detailed literature revision on the field allowed us to compile a panel of genes possibly generating a susceptibility to stroke, which could be a starting point for future research. Since stroke is a potentially preventable disease, the identification of genes associated with young stroke may promote novel prevention strategies and allow the identification of therapeutic disease targets.

In this paper, we discussed our recent experience with the use of computational modeling tools in studying the binding interaction of small molecular weight ligands with their protein targets. Specific examples discussed here include the interaction of estrogens with human protein disulfide isomerase (PDI) and its pancreas-specific homolog (PDIp), and the interaction of dietary flavonoids with human cyclooxygenase (COX) I and II. Using human PDIp as an example, biochemical analysis revealed that the estrogen-binding activity is only associated with PDIp’s b-b´ domain combination but not associated with the single b or b´ domain or any other domains. Homology modeling was then used to build a threedimensional structure of the human PDIp’s b-b´ fragment. Docking analyses predicted that a hydrogen bond, formed between the 3-hydroxyl group of estradiol and His278 of PDIp’s E2-binding site, is critical for the binding interaction. This binding model was then experimentally confirmed by a series of experiments, such as selective mutations of the predicted binding site amino acid residues and the selective modifications of the functional groups of the ligands. Similar combinatorial approaches were used successfully to identify the binding site structure of human PDI for estradiol and the binding site structures of human COX I and II for their phenolic co-substrates. The success with these combinatorial approaches provides the basis for using computational modeling-guided approaches in characterizing the ligand binding site structures of complex proteins whose structures are difficult to decipher with crystallographic studies.

G protein-coupled receptor (GPCR) (also known as seven-transmembrane domain receptor) superfamily represents the largest protein family in the human genome. These receptors respond to various physiological ligands such as photons, odors, pheromones, hormones, ions, and small molecules including amines, amino acids to large peptides and steroids. Thus, GPCRs are involved in many diseases and the target of around half of all conventional drugs. The physiological roles of free fatty acids (FFAs), in particular, long-chain FFAs, are important for the development of many metabolic disease including obesity, diabetes, and atherosclerosis. In the past half decade, deorphanization of several GPCRs has revealed that GPR40, GPR41, GPR43, GPR84 and GPR120 sense concentration of extracellular FFAs with various carbon chain lengths. GPR40 and GPR120 are activated by medium- and long-chain FFAs. GPR84 is activated by medium- chain, but not long-chain, FFAs. GPR41 and GPR43 are activated by short-chain FFAs. GPR40 is highly expressed in pancreatic beta cells and plays a crucial role in FFAs-induced insulin secretion. GPR120 is mainly expressed in enteroendocrine cells and plays an important role for FFAs-induced glucagon-like peptide-1. GPR43 is abundant in leukocytes and adipose tissue, whilst GPR41 is highly expressed in adipose tissue, the pancreas and leukocytes. GPR84 is expressed in leukocytes and monocyte/macrophage. This review aims to shed light on the physiological roles and development of drugs targeting these receptors.

In 1977 an unknown natural product was isolated from Streptomyces staurosporeus by Omura et al. during a search for new alkaloids present in actinomycetes and was given the name AM-2282. Later, the structure of AM-2282 was elucidated by single crystal X-ray analysis and renamed as staurosporine. It has been published that staurosporine and its analogues display strong inhibitory effect against a variety of kinases and a number of biological properties such as antifungal, antibacterial, and immunosuppressive activities. Despite strong inhibitory activity of staurosporine, a very high level of cross-reactivity makes it impossible to use staurosporine as a therapeutic agent. In the course of searching for other staurosporine-related compounds, a number of staurosporine analogues have been isolated from different microorganisms. In addition, a number of staurosporine analogues have been synthesized to improve the poor selectivity and target specificity of staurosporine which limited its clinical effectiveness. The review addresses staurosporine analogues from both microbial and synthetic sources and their biological activities.

Marine organisms have been developed as a new source of naturally occurring alkaloids. The bioactive scaffolds of marine alkaloids govern the cross-kingdom actions, possessing “unexpectedly” cytotoxic-related antitumor activities against human cancer cell lines. And the actions of marine alkaloids toward mammalian cells have been well substantiated by the recognition of their analogues as antitumor and enzyme modulatory agents. Different moieties of alkaloids target different cellular pathways. Structure-activity studies and docking analysis of marine alkaloids analogs attached importance to certain privileged moieties, and illustrated the mechanism of alkaloids’ functionalization in mammals. The fascinating observations prompted us to review five kinds of alkaloid-like moieties including thiazole, pyrroloquinon, oxazole, pyridine and indole, and illuminate suggestively their various roles in common cellular processes of human beings. Meanwhile, an hypothesis was made correlatively to explain the different mechanisms of their anticancer activities in human cell lines.

Influenza A virus, which has a high rate of morbidity and mortality, has become a serious threat to human health and society. Because of antigenic variation, the application of influenza vaccination is limited. Till now, the current antivirals are mainly against the M2 protein (such as adamantanes) and the neuraminidase (such as zanamivir and oseltamivir). However, many viral strains have developed resistance to these marketed antiviral drugs, and it is urgent to find new antivirals for the prevention and treatment of influenza. RNA polymerase that is crucial for the replication and transcription in the virus life cycle has been proved to be an effective target for design of new antivirals. In this review, we describe the recent progress of the structure, function, and inhibitors of the novel target.

This paper examines the formation and stability of nano-complexes that could provide a new therapeutic approach against HIV-1 infection. Poly(propylene imine) glycodendrimers decorated with 2nd generation cationic carbosilane dendrons were generated and their use in polyplex formation checked. Owing to their positively-charged terminal amino groups the hybrid glycodendrimers can bind anionic peptides. It was shown that they form nano-complexes with the HIV-derived peptides P24, Gp160 and Nef. Complexes 130-190 nm in size were formed in molar ratios (dendrimer/ peptide) of (3-4):1. These were sufficiently stable over time and at different pHs. The results obtained suggest that the hybrid dendrimers studied can be considered as alternative carriers for delivering HIV peptides to dendritic cells.

Vascular smooth muscle cell (VSMC) proliferation plays a central role in the pathogenesis of obesity-related atherosclerosis. The molecular mechanism of GA on oleic acid (OA)-induced proliferation of vascular smooth muscle cell is evaluated. Cells were treated with OA (150 μM), or co-treated with OA and GA (10-30 μM) for 48 h, MTT assay was performed for proliferation. Using flow cytometry analysis, the GA-treated cells caused an increase in G2/M phase. A decrease in cyclin B1 and cyclin-dependent kinase 1 (cdc2) and increase in kip/p27 and cip1/p21 were found by western blotting. Additional mechanistic studies showed that GA induced the activation of AMP-activated protein kinase (AMPK) and eNOS and the inhibition of fatty acid synthase (FAS) after stimulation with OA. Furthermore, the addition of compound C, a specific inhibitor of AMPK, reduced the activation of GA-mediated eNOS and NO production and increased the proliferation of cells. Inhibition of NOS by L-NAME had no further effect on VSMC proliferation. The present results indicate that GA was an effected and anti-atherogenic agent in VSMC. It attenuates cell cycle progression via AMPKmediated eNOS activation, which results in the production of NO and prevents atherosclerosis.