Current Medicinal Chemistry - Volume 21, Issue 12, 2014

Despite significant advances in early diagnosis and treatment, skin cancer is one of the leading causes of death. Photodynamic therapy (PDT) is a new therapeutic modality that is emerging as an important resource against malignant tumors. This strategy is based on the action of photosensitizers, i.e. of molecules which may accumulate preferentially inside tumor cells where they exert a cytotoxic effect after excitation by light at appropriate wavelengths. Some forms of skin cancers and also some non-tumor pathologies are now treated with PDT. Several compounds with photosensitizing activity have been identified, and some of these molecules are commercially available. Many photoactive principles are natural compounds. Numerous reviews in the last decade have focused on photodynamic therapy, its effects and applications, but less attention has been paid to plant extracts or molecules of natural origin studied for their phototoxic activity to date.This review critically examines the potential role of various plant extracts and naturally occurring compounds in the treatment of skin cancer. Both in vitro and in vivo effects of these agents, together with their known related cellular and molecular mechanisms, are presented and discussed.

Hepatitis C virus (HCV) infection affects about 160 million people worldwide. It is treated with pegylatedinterferon (peg-IFN) and ribavirin, and in the case of patients affected by genotype 1, also with a protease inhibitor (telaprevir or boceprevir). Despite a good success rate, IFN-based combinations are contraindicated in several patients (e.g. decompensated cirrhosis, patients with psychiatric disorders, severe heart diseases or autoimmune disorders) and are associated with frequent adverse events that ultimately reduce their use. Numerous oral drugs are in an advanced phase of clinical development, and in some cases, in IFN-free combinations. This review focuses on preclinical and clinical data regarding daclatasvir (BMS-790052), which is a highly selective HCV NS5A replication complex inhibitor effective against HCV genotypes 1, 2, 3 and 4. In vitro data show that daclatasvir exerts a very potent antiviral effect against several HCV genotypes. Its pharmacokinetics is optimal and allows once-a-day oral administration. Its adverse event profile is good. Clinical data regarding its efficacy in combination with peg-IFN, ribavirin or other direct antiviral agents are impressive (rates of sustained virological response range between 60% and 100% in treatment-naive patients). The only drawback of this drug appears to be a relatively low genetic barrier to resistance. In conclusion, daclatasvir, especially in combinations with other antiviral agents, is a very promising drug for the treatment of chronic hepatitis C.

The ongoing emergence of bacterial strains resistant to even third- and fourth-generation β-lactam antibiotics is one of the most pressing and challenging issues in clinical therapy. Furthermore, under the pressure of antibiotics used ubiquitously over the last 80 years, functional mutations and new resistances are continuously increasing. Therefore, new drugs and new approaches to the infections produced by multidrug-resistant Gram-negative bacteria are categorically necessary and expected by the scientific community. This review describes the most deleterious known extended-spectrum β- lactamases and the molecules now available for targeting bacterial infections. The active-site chemical and geometric properties that are potentially exploitable for the design of both broad-spectrum and selective compounds are described.

Cholesterol gallstone disease is one of the most prevalent and the most costly digestive diseases in Western countries. Its pathogenesis is a complex paradigm resulting from the interaction of genetic factors, hepatic hypersecretion of cholesterol, increased intestinal absorption of cholesterol, a constantly “supersaturated” bile, crystallization of biliary cholesterol, and gallbladder stasis. De novo cholesterol biosynthesis, biliary cholesterol output, and intestinal cholesterol absorption are therefore key steps involved in cholesterol homeostasis. Establishing the right pharmacological therapy for cholesterol gallstones is of major importance in Western healthcare systems. Certain drugs might independently influence cholesterol gallstone formation by blocking the 3-hydroxy-3-methylglutaryl-coenzyme A reductase and inhibiting cholesterol biosynthesis in the liver (statins) or blocking cholesterol absorption in the small intestine apical membrane by specifically inhibiting the Niemann-Pick C1-like 1 protein (ezetimibe). This review will focus on the possibility that statins and ezetimibe, by acting at different levels of cholesterol homeostasis, might represent novel therapeutic approaches to prevent cholesterol gallstones in selected subjects at risk.

It is widely believed that Alzheimer's disease pathogenesis is driven by the production and deposition of the amyloid-β peptide (Aβ) in the brain. In this study, we employ a combination of in silico and in vitro approaches to investigate the inhibitory properties of selected arginine-rich D-enantiomeric peptides (D-peptides) against amyloid aggregation. The D-peptides include D3, a 12-residue peptide with anti-amyloid potencies demonstrated in vitro and in vivo, RD2, a scrambled sequence of D3, as well as truncated RD2 variants. Using a global optimization method together with binding free energy calculations followed by molecular dynamics simulations, we perform a detailed analysis of D-peptide binding to Aβ monomer and a fibrillar Aβ structure. Results obtained from both molecular simulations and surface plasmon resonance experiments reveal a strong binding of D3 and RD2 to Aβ, leading to a significant reduction in the amount of β structures in both monomer and fibril, which was also demonstrated in Thioflavin T assays. The binding of the D-peptides to Aβ is driven by electrostatic interactions, mostly involving the D-arginine residues and Glu11, Glu22 and Asp23 of Aβ. Furthermore, we show that the anti-amyloid activities of the D-peptides depend on the length and sequence of the Dpeptide, its ability to form multiple weak hydrophobic interactions with Aβ, as well as the Aβ oligomer size.

Cationic peptides (polylysines and polyarginines) are being developed as drug delivery systems to nuclei. Therefore, a detailed description of tissue response changes upon the application of cationic peptides over intact basement membranes of excitable tissue is of interest in pharmacology. In this paper we examine the effects of two naturally occurring cationic peptides protamine (polyarginine) and crotamine (polylysine) on the optical profiles of retinal spreading depression waves (RSDs). This intrinsic optical signal (IOS), recorded non-invasively, provides information about dissipation of electrochemical gradients within the tissue and its metabolic consequences. Protamine at nanomolar range brought the tissue excitability to collapse without any signs of acute toxicity whereas crotamine, a known myotoxin from rattlesnake, decreased the tissue transparency and changed markedly the optical profiles of RSDs. Also, fluorescent crotamine was incorporated to Muller cells in a few minutes, suggesting a close membrane interaction. The optical changes brought about by crotamine were easily washed off. By contrast, the excitability collapse in presence of protamine lasted for at least two hours. Conclusions: we concluded that crotamine has fusogenic properties that alters ion transport in excitable tissue. Protamine effect seems to be similar to its effect on basement membrane of epithelium due to its property of making heteropolymers with heparan sulfate. The clinical syndrome expressed in mice after crotamine injection suggested excitotoxic CNS effects confirmed by the isolated retina experiments.