Current Medicinal Chemistry (v.21, #12)

Applications of Natural Compounds in the Photodynamic Therapy of Skin Cancer by M. Marrelli, G. Menichini, E. Provenzano, F. Conforti (1371-1390).
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 malignanttumors. This strategy is based on the action of photosensitizers, i.e. of molecules which may accumulate preferentially insidetumor cells where they exert a cytotoxic effect after excitation by light at appropriate wavelengths. Some forms ofskin cancers and also some non-tumor pathologies are now treated with PDT. Several compounds with photosensitizingactivity have been identified, and some of these molecules are commercially available. Many photoactive principles arenatural 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 activityto date.This review critically examines the potential role of various plant extracts and naturally occurring compounds inthe treatment of skin cancer. Both in vitro and in vivo effects of these agents, together with their known related cellularand molecular mechanisms, are presented and discussed.

Daclatasvir: The First of a New Class of Drugs Targeted Against Hepatitis C Virus NS5A by I. Gentile, F. Borgia, N. Coppola, A.R. Buonomo, G. Castaldo, G. Borgia (1391-1404).
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 (telapreviror 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 associatedwith frequent adverse events that ultimately reduce their use. Numerous oral drugs are in an advanced phase ofclinical development, and in some cases, in IFN-free combinations. This review focuses on preclinical and clinical dataregarding daclatasvir (BMS-790052), which is a highly selective HCV NS5A replication complex inhibitor effectiveagainst HCV genotypes 1, 2, 3 and 4. In vitro data show that daclatasvir exerts a very potent antiviral effect against severalHCV genotypes. Its pharmacokinetics is optimal and allows once-a-day oral administration. Its adverse event profileis 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-naïve patients). The onlydrawback of this drug appears to be a relatively low genetic barrier to resistance. In conclusion, daclatasvir, especially incombinations with other antiviral agents, is a very promising drug for the treatment of chronic hepatitis C.

The Inhibition of Extended Spectrum β-Lactamases: Hits and Leads by Davide Farina, Francesca Spyrakis, Alberto Venturelli, Simon Cross, Donatella Tondi, Maria Paola Costi (1405-1434).
The ongoing emergence of bacterial strains resistant to even third- and fourth-generation β-lactam antibiotics isone of the most pressing and challenging issues in clinical therapy. Furthermore, under the pressure of antibiotics usedubiquitously over the last 80 years, functional mutations and new resistances are continuously increasing. Therefore, newdrugs and new approaches to the infections produced by multidrug-resistant Gram-negative bacteria are categorically necessaryand 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 geometricproperties that are potentially exploitable for the design of both broad-spectrum and selective compounds are described.

Therapeutic Reflections in Cholesterol Homeostasis and Gallstone Disease: A Review by Agostino Di Ciaula, David Q.-H. Wang, Gabriella Garruti, Helen H. Wang, Ignazio Grattagliano, Ornella de Bari, Piero Portincasa (1435-1447).
Cholesterol gallstone disease is one of the most prevalent and the most costly digestive diseases in Westerncountries. Its pathogenesis is a complex paradigm resulting from the interaction of genetic factors, hepatic hypersecretionof cholesterol, increased intestinal absorption of cholesterol, a constantly “supersaturated” bile, crystallization of biliarycholesterol, and gallbladder stasis. De novo cholesterol biosynthesis, biliary cholesterol output, and intestinal cholesterolabsorption are therefore key steps involved in cholesterol homeostasis. Establishing the right pharmacological therapy forcholesterol gallstones is of major importance in Western healthcare systems. Certain drugs might independently influencecholesterol gallstone formation by blocking the 3-hydroxy-3-methylglutaryl-coenzyme A reductase and inhibiting cholesterolbiosynthesis in the liver (statins) or blocking cholesterol absorption in the small intestine apical membrane by specificallyinhibiting the Niemann-Pick C1-like 1 protein (ezetimibe). This review will focus on the possibility that statinsand ezetimibe, by acting at different levels of cholesterol homeostasis, might represent novel therapeutic approaches toprevent cholesterol gallstones in selected subjects at risk.

Amyloid Aggregation Inhibitory Mechanism of Arginine-rich D-peptides by O.O. Olubiyi, D. Frenzel, D. Bartnik, J.M. Gluck, O. Brener, L. Nagel-Steger, S.A. Funke, D. Willbold, B. Strodel (1448-1457).
It is widely believed that Alzheimer's disease pathogenesis is driven by the production and deposition of theamyloid-β peptide (Aβ) in the brain. In this study, we employ a combination of in silico and in vitro approaches to investigatethe 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 bindingfree energy calculations followed by molecular dynamics simulations, we perform a detailed analysis of D-peptide bindingto Aβ monomer and a fibrillar Aβ structure. Results obtained from both molecular simulations and surface plasmonresonance experiments reveal a strong binding of D3 and RD2 to Aβ, leading to a significant reduction in the amount of βstructures in both monomer and fibril, which was also demonstrated in Thioflavin T assays. The binding of the D-peptidesto 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 basementmembranes of excitable tissue is of interest in pharmacology. In this paper we examine the effects of two naturally occurringcationic peptides protamine (polyarginine) and crotamine (polylysine) on the optical profiles of retinal spreading depressionwaves (RSDs). This intrinsic optical signal (IOS), recorded non-invasively, provides information about dissipationof electrochemical gradients within the tissue and its metabolic consequences. Protamine at nanomolar range broughtthe 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 crotaminewas incorporated to Muller cells in a few minutes, suggesting a close membrane interaction. The optical changes broughtabout by crotamine were easily washed off. By contrast, the excitability collapse in presence of protamine lasted for atleast two hours. Conclusions: we concluded that crotamine has fusogenic properties that alters ion transport in excitabletissue. Protamine effect seems to be similar to its effect on basement membrane of epithelium due to its property of makingheteropolymers with heparan sulfate. The clinical syndrome expressed in mice after crotamine injection suggested excitotoxicCNS effects confirmed by the isolated retina experiments.