Current Medicinal Chemistry (v.22, #27)

Meet Our Editorial Board Member: by Wei Li (3109-3109).

Mycobacterium tuberculosis Low Molecular Weight Phosphatases (MPtpA and MPtpB): From Biological Insight to Inhibitors by Luisa Fanzani, Federica Porta, Fiorella Meneghetti, Stefania Villa, Arianna Gelain, Anna Paola Lucarelli, Emilio Parisini (3110-3132).
Mycobacterium tuberculosis (Mtb), the main aetiological agent of tuberculosis (TB) in humans, is estimated to cause nearly two million deaths every year. Despite their huge therapeutic value, existing antitubercular drugs have several shortcomings, such as for instance the insurgence of drug resistance, which is mostly triggered by lack of compliance during the lengthy treatment. Novel and more effective drugs against Mtb acting on new molecular targets are therefore in demand in order to reduce treatment time and address the severe issue related to the progressive loss of antibiotic efficacy. Mtb encodes for two low molecular weight tyrosine specific phosphatases (MPtpA and MPtpB) that are crucially involved in Mtb pathogenesis. While MPtpA interferes with phagosome acidification blocking its maturation, MPtpB disrupts host signal transduction cascades, causing immune response subversion in the host. The important role played by both MPtpA and MPtpB in host-pathogen interaction makes them appealing targets for TB drug discovery. Here, we provide an exhaustive review of the current knowledge on MPtpA and MPtpB characterization and role in TB pathogenesis. In particular, special emphasis is placed on all class of inhibitors that have been developed and studied to date; their binding mode, design strategies, biological activities, main pharmacophore features as well as the efforts to overcome the poor druggability of their target are summarized in detail.

Current Advances in Antitubercular Drug Discovery: Potent Prototypes and New Targets by Guilherme Felipe dos Santos Fernandes, Daniela Hartmann Jornada, Paula Carolina de Souza, Chung Man Chin, Fernando Rogério Pavan, Jean Leandro dos Santos (3133-3161).
Tuberculosis (TB) is an infectious disease caused by bacterium of the Mycobacterium genus, mainly by Mycobacterium tuberculosis (MTB). The World Health Organization aims to substantially reduce the number of cases in the coming years; however, the increased number of multidrug-resistant (MDR) and extremely drug-resistant (XDR) forms of the bacterium and the lack of treatment for latent tuberculosis are challenges to be overcome. In this review, we have identified the most potent compounds described in the literature during recent years with MIC values < 7 µM, low toxicity and a high selective index. In addition, emerging targets in MTB are presented to provide new perspectives for the discovery of new antitubercular drugs. This review aims to summarize the current advances in and promote insights into antitubercular drug discovery.

Nalmefene: A Novel Drug for an Old Disorder by Donatella Marazziti, Silvio Presta, Stefano Baroni, Francesco Mungai, Armando Piccinni, Federico Mucci, Liliana Dell'Osso (3162-3168).
Alcoholism is an increasing problem all over the world, and nowadays especially amongst teenagers. Although several drug treatments have been proposed for this condition, only a few have demonstrated a significant efficacy. Nalmefene, a novel compound that combines opioids mu-receptors antagonism and kappa-receptors partial agonism, was recently approved by the European Medicine Agency for the treatment of alcoholism. This drug can be very helpful in reducing the alcohol intake, and, as such, it can be considered one of the first and fundamental steps towards alcohol abstinence. The aim of this review is to discuss and comment on the available literature on nalmefene, as well as on novel treatment strategies of this condition (and perhaps of other addictions) opened by this latest pharmacological approach.

Unfolded Protein Response and PERK Kinase as a New Therapeutic Target in the Pathogenesis of Alzheimer's Disease by Wioletta Rozpedek, Lukasz Markiewicz, J. Alan Diehl, Dariusz Pytel, Ireneusz Majsterek (3169-3184).
Recent evidence suggests that the development of Alzheimer's disease (AD) and related cognitive loss is due to mutations in the Amyloid Precursor Protein (APP) gene on chromosome 21 and increased activation of eukaryotic translation initiation factor-2α (eIF2α) phosphorylation. The high level of misfolded and unfolded proteins loading in Endoplasmic Reticulum (ER) lumen triggers ER stress and as a result Unfolded Protein Response (UPR) pathways are activated. Stress-dependent activation of the protein kinase RNA-like endoplasmic reticulum kinase (PERK) leads to the significant elevation of phospho-eIF2α. That attenuates general translation and, on the other hand, promotes the preferential synthesis of Activating Transcription Factor 4 (ATF4) and secretase β (BACE1) - a pivotal enzyme responsible for the initiation of the amyloidogenic pathway resulting in the generation of the amyloid β (Aβ) variant with high ability to form toxic senile plaques in AD brains. Moreover, excessive, long-term stress conditions may contribute to inducing neuronal death by apoptosis as a result of the overactivated expression of pro-apoptotic proteins via ATF4. These findings allow to infer that dysregulated translation, increased expression of BACE1 and ATF4, as a result of eIF2α phosphorylation, may be a major contributor to structural and functional neuronal loss resulting in memory impairment. Thus, blocking PERK-dependent eIF2α phosphorylation through specific, small-molecule PERK branch inhibitors seems to be a potential treatment strategy for AD individuals. That may contribute to the restoration of global translation rates and reduction of expression of ATF4 and BACE1. Hence, the treatment strategy can block accelerated β -amyloidogenesis by reduction in APP cleaving via the BACE1-dependent amyloidogenic pathway.

The Interest of Folic Acid in Targeted Photodynamic Therapy by Aurelie Stallivieri, Francis Baros, Gulim Jetpisbayeva, Bauyrzhan Myrzakhmetov, Celine Frochot (3185-3207).
Photodynamic therapy is an alternative to chemotherapy and radiotherapy for cancer treatment. PDT is clinically applied to treat age-related macular degeneration and several types of cancer. Most of the time, the selectivity of the treatment is brought about by the application of light. Another strategy to improve selectivity is to design and synthesize targeted photosensitizers or nanoparticles, which can identify and selectively accumulate within tumor tissues. This review presents our inventory of all the data concerning the use of folic acid as a promising targeting unit to improve the selectivity of photosensitizers to folic acid receptors. We will discuss the strategies that are developed to couple folic acid to photosensitizers or nanoparticles as well as the influence of the presence of folic acid on the objects' photophysical properties and their effects on selectivity and phototoxicity in vitro and in vivo.