Current Medicinal Chemistry (v.18, #16)

STAT-3 Inhibitors: State of the Art and New Horizons for Cancer Treatment by A. Lavecchia, C. Di Giovanni, E. Novellino (2359-2375).
The signal transducers and activators of transcription (STATs) include a class of cytoplasmic signaling proteins whose role inthe regulation of cell growth and survival is mediated by phosphorylation of a critical tyrosine residue within the STAT protein. Thisoccurs in response to cytokines and growth factors modulating the expression of specific target genes. In particular, phosphorylationinduces STAT:STAT dimer formation between two monomers, via reciprocal phosphoTyr (pTyr)-SH2 domain interactions. To date,seven members of the STAT family, all with different roles, have been identified in mammals. After dimerization, phosphorylatedSTATs enter the nucleus and, working co-ordinately with other transcriptional co-activators and transcription factors, induce increasedtranscriptional initiation. In healthy human and animal cells, ligand-dependent activation of STATs is a transient process, lasting forseveral minutes to several hours. In contrast, in many cancerous cell lines and tumors, where growth factor dysregulation is frequently atthe heart of cellular transformation, the STAT proteins (in particular STAT1, 3 and 5) are persistently tyrosine-phosphorylated oractivated; abnormal levels of STAT3 activation have been observed in breast, ovarian, prostate, hematological and head and neck cancercell lines. Thus, in this review, we examine the most important classes of agents designed to disrupt STAT3 signaling, with particularregard to STAT3 dimerization inhibitors, which could play a significant role in the future of cancer and adjuvant cancer therapies.

HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) bind to an allosteric site on reverse transcriptase (RT) and area key component of highly active anti-retroviral therapy (HAART) combination regimen for clinical treatment of HIV/AIDS. However,the rapid emergence of drug resistance has limited NNRTIs’ clinical option. Therefore, there is an urgent need for the design anddevelopment of new and safe NNRTIs that are specifically active against drug-resistant viral strains. DABOs family is one representativeof the reported potent HIV-1 NNRTIs, with robust anti-HIV-1 activity against both the wild-type (wt) and drug-resistant isolates carryingmultiple RT gene mutations. Three generations of DABO analogues have been studied up to now, i.e.: dihydroalkyloxybenzyloxopyrimidines(O-DABOs), dihydroalkylthiobenzyloxopyrimidines (S-DABOs) and dihydroalkylaminodifluorobenzyloxopyrimidines(N-DABOs), from which many promising DABOs are under developed. The recent research of the DABOs family inantiviral activity, structure activity relationships (SAR), and interaction model with the HIV-1 RT are reviewed in this paper.

Interactions Between Clopidogrel and Proton Pump Inhibitors: A Review of Evidence by C. Munoz-Esparza, E. Jover, D. Hernandez-Romero, D. Saura, M. Valdes, G.Y.H. Lip, F. Marin (2386-2400).
Clopidogrel is a thienopyridine, which inhibits the platelet P2Y adenosine diphosphate (ADP) receptor termed P2Y12. It istaken as a prodrug that requires biotransformation to an active metabolite by cytochrome P450 (CYP) isoenzymes. In addition, esterasesshunt the majority of clopidogrel to an inactive pathway, whilst the remaining prodrug requires two separate CYP-dependent oxidativesteps. PPIs might diminish the antiplatelet effects and the clinical effectiveness of clopidogrel possibly through inhibition of CYP2C19and CYP3A4 isoenzymes. Treatment with clopidogrel and aspirin decreases recurrent cardiovascular events after an acute coronary syndrome. However, an inherentincrement of major bleeding is also associated with antiplatelet therapy, as well as dyspepsia with aspirin. Also, major bleeding has beenassociated with high risk for ischemic events and mortality. For this reason, a proton pump inhibitor (PPI) is often co-prescribed toreduce the risk of gastrointestinal tract bleeding, but its concomitant use might reduce the inhibitory effect of clopidogrel on plateletaggregation. Nevertheless, doubts exist about the possible interaction of concomitant PPI use that may reduce the inhibitory effect ofclopidogrel on platelet aggregation. Indeed, there is some controversy with regard to the true risk of cardiovascular adverse events arisingfrom a potential drug-drug interaction between clopidogrel and PPI. In this article, we will review the current status and controversies inrelation to a possible interaction between clopidogrel and PPIs.

Mycoses are still one of the most problematic illnesses worldwide, especially affecting immunocompromised individuals. Thedevelopment of novel antifungal drugs is becoming more demanding every day, since existing drugs either have too many side effects orthey tend to lose effectiveness due to the resistant fungal strains. In this scenario, Candida albicans is still the main fungal pathogenisolated in hospitals. Pathogenicity results essentially from modifications of the host defense mechanisms that secondarily initiatetransformations in the fungal behavior. The pathogenesis of C. albicans is multifactorial and different virulence attributes are importantduring the various stages of infection. Some virulence factors, like the secreted aspartic proteases (Saps), play a role in several infectionstages and the inhibition of one of the many stages may contribute to the containment of the pathogen and thus should help in thetreatment of disease. Therefore, Saps are potential targets for the development of novel anti-C. albicans drugs. Herein, we review thebeneficial properties of pepstatin A and aspartic-type protease inhibitors used in the anti-human immunodeficiency virus chemotherapyon C. albicans, with particular emphasis in the effects on Sap activity, proliferation, morphogenesis (yeasts into mycelia transformation),ultrastructural architecture, adhesion to mammalian cells and abiotic materials, modulation of unrelated virulence factors (e.g., surfaceglycoconjugates, lipases and sterol), experimental candidiasis infection as well as synergistic properties when conjugated with classicalantifungals. Collectively, these positive findings have stimulated the search for novel natural and/or synthetic pharmacologicalcompounds with anti-aspartic protease properties against the human opportunistic fungus C. albicans.

Protein-protein interactions play a major role in almost all biological pathways and thus, these interactions have a profoundimpact on the pathogenesis of diseases. The ability to modulate protein-protein interactions with small molecules is an important andrapidly growing area in the field of medicinal chemistry. One of the most common secondary protein structures that are involved inprotein-protein interactions are α-helices. Thus, a common approach towards developing inhibitors of protein-protein interactions is todesign non-peptidic small molecules that mimic the spatial orientations of the side chains of an α-helix. In this review, we will discuss avariety of small molecules including terephenyls, terephthalamides, benzamides, enaminones, benzoylureas, pyridines, imidazoles,thiazoles, pyridazines, piperazines, oxopiperazines and diphenylindanes that have been published from 2005-2010 as small molecule α-helical mimetics.

Branched Peptides for the Modulation of Protein-Protein Interactions: More Arms are Better than One? by M. Ruvo, A. Sandomenico, L. Tudisco, S. De Falco (2429-2437).
Combinatorial peptide libraries from synthetic or biological sources have been largely used in the last two-decades with theaim of identifying bioactive peptides that specifically bind proteins and modulate their interactions with other protein partners.Differently from biological libraries, synthetic methods allow the development of different kinds of libraries based on two maincharacteristics: i) the use of building blocks and chemical bonds different from those naturally occurring and ii) the possibility ofdesigning scaffolds with non-linear shapes, as cyclic and branched structures. These two features, alone or in combination, haveincreased the chemical and structural diversity of peptide libraries expanding the offer of collections for the screenings.Here we describe our and other experiences with branched peptides and the results obtained in the last fifteen years. These clearlyindicate how the use of short multimerized peptides can represent a successful approach for different applications ranging from affinitychromatography to the modulation of protein-protein interactions in different biological contexts.

Recent Developments in the Synthesis and Biological Activity of Muramylpeptides by K. Dzierzbicka, A. Wardowska, P. Trzonkowski (2438-2451).
Derivatives of muramyl dipeptide (MDP) are considered as immunostimulants and adjuvants in the immunotherapy of cancerand infections. The interest in these compounds is mainly related to a high variety of their structure and biological properties. Here, wedescribe the synthesis and biological activity of several recently developed classes of MDP analogues. We also report potential of theseanalogues in the treatment of cancer and infectious diseases in experimental systems and cancer patients.

Regional Grey Matter Loss and Brain Disconnection Across Alzheimer Disease Evolution by M. Bozzali, A. Padovani, C. Caltagirone, B. Borroni (2452-2458).
It is becoming increasingly clearer that the clinical manifestations of Alzheimer’s disease (AD) are not only associated withregional grey matter (GM) damage, but also with abnormal integration between cortical brain regions by disconnection mechanism. Thisconcept comes from the evidence that white matter (WM) damage (as assessed by diffusion MR imaging) can be observed in patientswith AD since the early clinical stages, and it correlates with clinical measures of cognitive disability. In this perspective, severalfunctional imaging studies, based on PET and resting state fMRI, have provided evidence that brain hypometabolism/disconnection mayprecede the occurrence of GM atrophy in certain regions of AD brains, such as the cingulate cortex. The cingulum represents the mostprominent WM tract of the limbic system, being directly connected to the medial temporal lobe structures. Therefore, this structure likelycontributes to changes in functional connectivity observed within the so called default-mode network of AD patients, and its damage islikely to play a remarkable role in the conversion from mild cognitive impairment (MCI) to dementia. Nowadays, the combination ofseveral neuroimaging techniques that provide both, measures of regional GM loss and measures of functional and structural connectivityoffer the opportunity to investigate in vivo the pathophysiological changes of brain tissue modifications across the clinical evolution ofAD. This paper reviews the main MR based methods of investigation of brain tissue involvement in patients with AD and MCI, and therole they have played in clarifying the differential contribution of GM damage and brain disconnection to AD pathophysiology. Thissubject seems to be relevant for both, speculative aspects of neurology and application to clinical trials.

Removing Protein Aggregates: The Role of Proteolysis in Neurodegeneration by D.A.T. Nijholt, L. De Kimpe, H.L. Elfrink, J.J.M. Hoozemans, W. Scheper (2459-2476).
A common characteristic of neurodegenerative diseases like Alzheimer’s disease (AD), Parkinson’s disease (PD) andHuntington’s disease (HD) is the accumulation of protein aggregates. This reflects a severe disturbance of protein homeostasis, theproteostasis. Here, we review the involvement of the two major proteolytic machineries, the ubiquitin proteasome system (UPS) and theautophagy/lysosomal system, in the pathogenesis of neurodegenerative diseases. These proteolytic systems cooperate to maintain theproteostasis, as is indicated by intricate cross talk. In addition, the UPS and autophagy are regulated by stress pathways that are activatedby disturbed proteostasis, like the unfolded protein response (UPR). We will specifically discuss how these proteolytic pathways areaffected in neurodegenerative diseases. We will show that there is a differential involvement of the UPS and autophagy in differentneurodegenerative disorders. In addition, the proteolytic impairment may be primary or secondary to the pathology. These differenceshave important implications for the design of therapeutic strategies. The opportunities and caveats of targeting the UPS andautophagy/lysosomal system as a therapeutic strategy in neurodegeneration will be discussed.

Posttranslational Modifications as Versatile Regulators of Parkin Function by E. Rubio de la Torre, P.Gomez-Suaga, M. Martinez-Salvador, S. Hilfiker (2477-2485).
Parkin functions as an E3 ubiquitin ligase that monoubiquitylates and polyubiquitylates proteins to regulate a variety ofcellular processes. It appears that parkin functions as a multipurpose neuroprotectant in a number of toxic paradigms, and loss of parkin’sE3 ligase activity seems to play a pathogenic role in both inherited and sporadic Parkinson’s disease (PD). Increasing evidence indicatesthat posttranslational modifications play a major role in regulating parkin’s catalytic activity, solubility, substrate selection or subcellularlocalization. As some of these modification events are subject to pharmacological interventions, these findings may allow for newapproaches in preventing or delaying PD onset and/or progression. Here, we review how posttranslational modifications can regulate thisunique multifaceted ubiquitin ligase which plays a crucial role for the survival of dopaminergic neurons.

Mechanisms of Resistance to Photodynamic Therapy by A. Casas, G. Di Venosa, T. Hasan, Al. Batlle (2486-2515).
Photodynamic therapy (PDT) involves the administration of a photosensitizer (PS) followed by illumination with visible light,leading to generation of reactive oxygen species. The mechanisms of resistance to PDT ascribed to the PS may be shared with the generalmechanisms of drug resistance, and are related to altered drug uptake and efflux rates or altered intracellular trafficking. As a second step,an increased inactivation of oxygen reactive species is also associated to PDT resistance via antioxidant detoxifying enzymes andactivation of heat shock proteins. Induction of stress response genes also occurs after PDT, resulting in modulation of proliferation, celldetachment and inducing survival pathways among other multiple extracellular signalling events. In addition, an increased repair ofinduced damage to proteins, membranes and occasionally to DNA may happen. PDT-induced tissue hypoxia as a result of vasculardamage and photochemical oxygen consumption may also contribute to the appearance of resistant cells.The structure of the PS is believed to be a key point in the development of resistance, being probably related to its particular subcellularlocalization. Although most of the features have already been described for chemoresistance, in many cases, no cross-resistance between PDT andchemotherapy has been reported. These findings are in line with the enhancement of PDT efficacy by combination with chemotherapy.The study of cross resistance in cells with developed resistance against a particular PS challenged against other PS is also highly complexand comprises different mechanisms. In this review we will classify the different features observed in PDT resistance, leading to a comparison with the mechanisms mostcommonly found in chemo resistant cells.