Current Medicinal Chemistry - Volume 27, Issue 23, 2020

Background: Lomitapide (Juxtapid® in US and Lojuxta® in Europe) is the first developed inhibitor of the Microsomal Triglyceride Transfer Protein (MTP) approved as a novel drug for the management of Homozygous Familial Hypercholesterolemia (HoFH). It acts by binding directly and selectively to MTP thus decreasing the assembly and secretion of the apo-B containing lipoproteins both in the liver and in the intestine. Aims: The present review aims at summarizing the recent knowledge on lomitapide in the management of HoFH. Results: The efficacy and safety of lomitapide have been evaluated in several trials and it has been shown a reduction of the plasma levels of Low-Density Lipoprotein Cholesterol (LDL-C) by an average of more than 50%. Although the most common side effects are gastrointestinal and liver events, lomitapide presents generally with a good tolerability and satisfactory patients compliance. Recently, in Europe, to evaluate the long-term safety and efficacy of lomitapide, the LOWER registry (ClinicalTrials.gov Identifier: NCT02135705) has been established in order to acquire informations on HoFH lomitapidetreated patients from “real life” clinical practice. Furthermore, the observation that lomitapide decreases triglyceride levels may be considered for patients affected by severe forms of hypertriglyceridemia who undergo recurrent episodes of pancreatitis and are poor responders to conventional treatment. Conclusion: Lomitapide represents an innovative and efficacious drug for the treatment of HoFH. Longterm safety data, treatment of pediatric and pregnant HoFH patients and management of severe hypertriglyceridemia still require further investigations.

Background: Migraine may be described as a headache with moderate to extreme pain that is often accompanied by incapacitating neurological symptoms. It is estimated that 12% of the world population suffers from migraine. Although a number of drugs have been used for treatment of migraine, most of these are not effective for every patient and may have undesirable side-effects. Thus, there is an enormous unmet need in current migraine therapy for discovering safer and more effective agents. Methods: The information summarized in this review was obtained through extensive literature review and search of relevant books and articles with the use of Web of Knowledge and SciVerse Scopus databases. Results: Greater understanding of the molecular mechanisms underlying the etiopathogenesis of migraine is helpful in identifying novel targets for antimigraine drugs such as cannabinoid, histamine, and melatonin receptors. In the past, natural product-derived constituents have served as an invaluable source of numerous medicinally useful antimigraine agents and it may be expected that further promising drug candidates from natural products will be discovered for antimigraine pharmacotherapy with better efficacy and fewer adverse-effects. Conclusion: The discovery of novel targets in migraine therapy has opened new horizons for compounds that have not been clinically tested or that previously failed in clinical trials as potential antimigraine drugs. Ginkgolide B, melatonin, histamine, oxytocin, various ribosomal peptide toxins, kavalactones, devil’s claw-derived compounds, salvinorin A and petasin are among those agents that show considerable promise as novel drugs in migraine prevention and treatment. It is necessary to conduct more research to better understand their antimigraine action, to confirm their effectiveness and safety, and to introduce them into clinical practice.

Topical administration of drugs presents some advantages over other routes; the drug can be administered in the anatomical region to be treated, limiting the systemic distribution and side effects. However, the structure of the skin makes it a highly effective barrier to drug permeation. Amongst the strategies to overcome this obstacle, liposomes are interesting vehicles for delivering the drugs into the skin, the synovial cavity or other regions affected by inflammatory or degenerative conditions. Liposomes are lipid carriers of nanometric size formed by phospholipid bilayers. They have the advantages of preparation feasibility and biological compatibility associated with the possibility of carrying either lipophylic and/or hydrophylic compounds, and have been extensively used in various drug delivery systems, for drug targeting, controlled release and permeation enhancement of drugs. Conventional liposomes are not very stable and not suitable for dermal administration after topical application, since they accumulate on the skin surface due to the rigidity of the lipid layers and suffer dehydration, culminating in their fragmentation. Other formulations have emerged in the meantime, such as transfersomes, niosomes or ethosomes. The present work consists of a review on the published scientific papers regarding the development of liposomal formulations containing non-steroidal anti-inflammatory drugs for the purpose of relieving the symptomatology of inflammatory and degenerative ailments. The exposition summarizes data relating to liposome type, composition, preparation method, liposome characterization, topical vehicle used, in vitro permeation studies performed, in vivo anti-inflammatory assays carried out and results obtained in the different studies published in the last five years.

Background: The human Monoamine Transporters (hMATs), primarily including hSERT, hNET and hDAT, are important targets for the treatment of depression and other behavioral disorders with more than the availability of 30 approved drugs. Objective: This paper is to review the recent progress in the binding mode and inhibitory mechanism of hMATs inhibitors with the central or allosteric binding sites, for the benefit of future hMATs inhibitor design and discovery. The Structure-Activity Relationship (SAR) and the selectivity for hit/lead compounds to hMATs that are evaluated by in vitro and in vivo experiments will be highlighted. Methods: PubMed and Web of Science databases were searched for protein-ligand interaction, novel inhibitors design and synthesis studies related to hMATs. Results: Literature data indicate that since the first crystal structure determinations of the homologous bacterial Leucine Transporter (LeuT) complexed with clomipramine, a sizable database of over 100 experimental structures or computational models has been accumulated that now defines a substantial degree of structural variability hMATs-ligands recognition. In the meanwhile, a number of novel hMATs inhibitors have been discovered by medicinal chemistry with significant help from computational models. Conclusion: The reported new compounds act on hMATs as well as the structures of the transporters complexed with diverse ligands by either experiment or computational modeling have shed light on the poly-pharmacology, multimodal and allosteric regulation of the drugs to transporters. All of the studies will greatly promote the Structure-Based Drug Design (SBDD) of structurally novel scaffolds with high activity and selectivity for hMATs.

Red and NIR light-responsive polymeric nanocarriers capable of on-demand drug delivery have gained tremendous attention for their great potential in cancer therapy. Various strategies have been applied to fabricate such nanocarriers, and they have demonstrated significant therapeutic efficacy and minimal toxicity to normal tissues. Here, we will review the current developments in various red and NIR light-responsive polymeric nanocarriers with respect to their use in on-demand drug delivery, including facilitation of drug internalization and boosting of drug release at targeted sites. We summarize their components and design strategies, and highlight the mechanisms by which the photoactivatable variations enhance drug uptake and drug release. We attempt to provide new insights into the fabrication of red and NIR light-responsive polymeric nanocarriers for on-demand drug delivery.

Nanoparticles are one of the most commonly used systems for imaging or therapeutic drug delivery. Exosomes are nanovesicular carriers that transport cargo for intercellular communication. These nanovesicles are linked to the pathology of some major diseases, in some cases with a central role in their progression. The use of these carriers to transport therapeutic drugs is a recent and promising approach to treat diseases such as cancer and Alzheimer disease. The physiological production of these structures is limited impairing its collection and subsequent purification. These drawbacks inspired the search for mimetic alternatives. The collection of exosome-like nanoparticles from plants can be a good alternative, since they are easier to extract and do not have the drawbacks of those produced in animal cells. Both natural and synthetic exosome-like nanoparticles, produced from serial extrusion of cells or by bottom up synthesis, are currently some of the most promising, biocompatible, high efficiency systems for drug delivery.

Zika Virus (ZIKV) belongs to the class of flavivirus that can be transmitted by Aedes mosquitoes. The number of Zika virus caused cases of acute infections, neurological disorders and congenital microcephaly are rapidly growing and therefore, in 2016, the World Health Organization declared a global “Public Health Emergency of International Concern”. Anti-ZIKV therapeutic and vaccine development strategies are growing worldwide in recent years, however, no specific and safe treatment is available till date to save the human life. Currently, development of peptide therapeutics against ZIKV has attracted rising attention on account of their high safety concern and low development cost, in comparison to small therapeutic molecules and antibody-based anti-viral drugs. In present review, an overview of ZIKV inhibition by peptide-based inhibitors including E-protein derived peptides, antimicrobial peptides, frog skin peptides and probiotic peptides has been discussed. Peptides inhibitors have also been reported to act against NS5, NS2B-NS3 protease and proteasome in order to inhibit ZIKV infection. Recent advances in peptide-based therapeutics and vaccine have been reviewed and their future promise against ZIKV infections has been explored.

Molecular imaging techniques apply sophisticated technologies to monitor, directly or indirectly, the spatiotemporal distribution of molecular or cellular processes for biomedical, diagnostic, or therapeutic purposes. For example, Single-Photon Emission Computed Tomography (SPECT) and Positron Emission Tomography (PET) imaging, the most representative modalities of molecular imaging, enable earlier and more accurate diagnosis of cancer and cardiovascular diseases. New possibilities for noninvasive molecular imaging in vivo have emerged with advances in bioorthogonal chemistry. For example, tetrazine-related Inverse Electron Demand Diels-Alder (IEDDA) reactions can rapidly generate short-lived radioisotope probes in vivo that provide strong contrast for SPECT and PET. Here, we review pretargeting strategies for molecular imaging and novel radiotracers synthesized via tetrazine bioorthogonal chemistry. We systematically describe advances in direct radiolabeling and pretargeting approaches in SPECT and PET using metal and nonmetal radioisotopes based on tetrazine bioorthogonal reactions, and we discuss prospects for the future of such contrast agents.

Persuasive evidence has been presented linking the infiltration of Tumor-Associated Macrophages (TAMs) with the driving force of tumorigenesis and in the suppression of antitumor immunity. In this context CSF1R, the cellular receptor for Colony Stimulating Factor-1 (CSF1) and Interleukin 34 (IL-34), occupies a central role in manipulating the behavior of TAMs and the dysregulation of CSF1R signaling has been implicated in cancer progression and immunosuppression in many specific cancers. Consequently, CSF1R kinase has been a target of great interest in cancer treatment and significant research efforts have focused on the development of smallmolecule CSF1R inhibitors. In this review, we highlight current progress on the development of these small molecule CSF1R inhibitors as anticancer agents. Special attention is paid to the compounds available in advanced clinical trials.

Expressed by a variety of plants, fungi and bacteria, the urease enzyme is directly associated with the virulence factor of many bacteria, including Helicobacter pylori, a gram-negative bacterium related to several gastrointestinal diseases and responsible for one of the most frequent bacterial infections throughout the world. The Helicobacter pylori Urease (HPU) is a nickel-dependent metalloenzyme expressed in response to the environmental stress caused by the acidic pH of the stomach. The enzyme promotes the increase of gastric pH through acid neutralization by the products of urea hydrolysis, then critically contributing to the colonization and pathogenesis of the microorganism. At the same time, standard treatments for Helicobacter pylori infections have limitations such as the increasing bacterial resistance to the antibiotics used in the clinical practice. As a strategy for the development of novel treatments, urease inhibitors have proved to be promising, with a wide range of chemical compounds, including natural, synthetic and semisynthetic products to be researched and potentially developed as new drugs. In this context, this review highlights the advances in the field of HPU inhibition, presenting and discussing the basis for the research of new molecules aiming at the identification of more efficient therapeutic entities.