Current Medicinal Chemistry - Volume 28, Issue 37, 2021

The Mediterranean diet is worldwide recognized as a good prototype of nutrition due to the conspicuous intake of olive oil, nuts, red wine, legumes, fruit, and vegetables, all fundamental elements rich in antioxidant substances and polyphenols. Polyphenols are a wide range of phytochemicals and/or synthetic chemical compounds with proven beneficial properties for human health. In the present review, we critically summarize the wellcharacterized antioxidant and anti-inflammatory properties of polyphenols contained in the olives and extra virgin olive oil and of resveratrol, a non-flavonoid phenolic compound. We discuss the potential use of these polyphenols as pharmaceutical formulations for the treatment of human diseases. We also show the emerging importance of their consumption in the prevention and management of crucial neurodegenerative conditions (alcohol-related brain disorders and aging) and in neuromuscular disorders (Spinal Muscular Atrophy and Amyotrophic Lateral Sclerosis and Duchenne Muscular Dystrophy), where oxidative stress plays a predominant role.

Background: The main protease of SARS-CoV-2 (M^pro) is one of the targets identified in SARS-CoV-2, the causative agent of COVID-19. The application of X-ray diffraction crystallography made available the three-dimensional structure of this protein target in complex with ligands, which paved the way for docking studies. Objective: Our goal here is to review recent efforts in the application of docking simulations to identify inhibitors of the M^pro using the program AutoDock4. Methods: We searched PubMed to identify studies that applied AutoDock4 for docking against this protein target. We used the structures available for M^pro to analyze intermolecular interactions and reviewed the methods used to search for inhibitors. Results: The application of docking against the structures available for the M^pro found ligands with an estimated inhibition in the nanomolar range. Such computational approaches focused on the crystal structures revealed potential inhibitors of M^pro that might exhibit pharmacological activity against SARS-CoV-2. Nevertheless, most of these studies lack the proper validation of the docking protocol. Also, they all ignored the potential use of machine learning to predict affinity. Conclusion: The combination of structural data with computational approaches opened the possibility to accelerate the search for drugs to treat COVID-19. Several studies used AutoDock4 to search for inhibitors of M^pro. Most of them did not employ a validated docking protocol, which lends support to critics of their computational methodology. Furthermore, one of these studies reported the binding of chloroquine and hydroxychloroquine to M^pro. This study ignores the scientific evidence against the use of these antimalarial drugs to treat COVID-19.

We provide a brief review of the significance of platelets, mitochondria, vitamin D, serotonin, and the gut microbiome in COVID-19. We hypothesize that hyperactive platelets and mitochondrial dysfunction, as well as low vitamin D level, gut dysbiosis, and increased serum serotonin produced by enterochromaffin cells, may all represent important aspects in the pathophysiology of COVID-19.

Reactive oxygen/nitrogen species (ROS/RNS) are produced physiologically by several mechanisms, especially during the inflammatory response. However, their overproduction can lead to the evolution of conditions known as oxidative/nitrosative stress, resulting in the establishment of chronic inflammatory diseases. Chalcones are considered as a class of flavonoids having the molecular pattern 1,3-diaryl-2-propen-1-one. In the last few years, the antioxidant property of chalcones has been extensively studied, mainly due to their ability to inhibit the production or scavenging ROS/RNS. The antioxidant activity of chalcones, focusing on the production of ROS/RNS during the inflammatory response, is demonstrated and discussed in the present review. This literature revision was based on the modulatory effects of chalcones against different enzymes, such as superoxide dismutase (SOD), nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, catalase (CAT), myeloperoxidase (MPO) and inducible nitric oxide synthase (iNOS), and, in the scavenging of ROS/RNS. Whenever possible, the structure-activity relationship (SAR) was established. Through the analysis accomplished in this review, it can be observed that the presence of substituents, e.g. hydroxyl, methoxyl, prenyl, and halogen atoms in the chalcones scaffold, often occurs and can improve their modulatory activities, namely, in the production of ROS/RNS during the inflammatory response.

Striatal-enriched protein tyrosine phosphatase (STEP) is exclusively expressed in the central nervous system and regulates various neuronal signaling factors through the dephosphorylation of different substrates. Dysregulated expression or uncontrollable enzymatic activity of STEP contributes to neurological disorders such as Alzheimer's disease, which makes it a promising pharmaceutical target. Herein, we have reviewed the structure and biological functions of STEP, as well as the recent development of smallmolecule STEP modulators. We hope this review will provide a reference for the further development of more potent and selective STEP inhibitors for the treatment of nervous system diseases.

Background: Glioblastoma constitutes the most frequent and aggressive primary malignant brain tumor in adults. Despite the advances in its treatment, its prognosis remains very poor. Gene therapy has been proposed as a complementary treatment since it may overcome the problem of the blood-brain barrier for systemic therapies, allowing to target tumor cells and their tumor microenvironment locally, without affecting the normal brain parenchyma. In comparison with viral vectors, non-viral vectors became an attractive tool due to their reduced potential of biosafety risks, lower cost, higher availability, and easy storage. Objective: In this article, we aimed to outline the current preclinical and clinical developments of non-viral delivery systems for therapeutic transgene delivery in malignant gliomas. Conclusion: Non-viral vectors are efficient tools for gene delivery since they exhibit reduced non-specific cytotoxicity and can go through several modifications in order to achieve high tumor tropism and the ability to cross the blood-brain barrier to access the tumor mass. However, further evaluations in preclinical models and clinical trials are required in order to translate it into the neuro-oncology clinic.

There have been intense research interests in sirtuins since the establishment of their regulatory roles in a myriad of pathological processes. In the last two decades, many research efforts have been dedicated to the development of sirtuin modulators. Although synthetic sirtuin modulators are the focus, natural modulators remain an integral part to be further explored in this area as they are found to possess therapeutic potential in various diseases, including cancers, neurodegenerative diseases, and metabolic disorders. Owing to the importance of this cluster of compounds, this review gives a current stand on the naturally occurring sirtuin modulators, associated molecular mechanisms, and their therapeutic benefits. Furthermore, comprehensive data mining resulted in detailed statistical data analysis pertaining to the developmental trend of sirtuin modulators from 2010-2020. Lastly, the challenges and future prospects of natural sirtuin modulators in drug discovery will also be discussed.

Dengue, the oldest and the most prevalent mosquito-borne illness, is caused by the dengue virus (DENV), from the family of Flaviviridae. It infects approximately 400 million individuals per annum, with approximately half of the global population residing in high-risk areas. The factors attributed to the geographic expansion of dengue, include urbanization, population density, modern means of transportation, international travels, habit modification, climate change, virus genetics, vector capacity, and poor vector control. Despite the significant progress made in the past against dengue, no effective antiviral therapy is currently available. Among the structural and non-structural proteins encoded by DENV genome, the NS2B−NS3 protease complex is amongst the extensively studied targets for the development of antiviral therapeutics owing to its multiple roles in virus life cycle. Furthermore, protease inhibitors were found to be successful in Hepatitis C Virus (HCV) and Human Immunodeficiency Virus (HIV). Likewise, several peptidic, peptide derived/peptidomimetic, and small molecules inhibitors have been identified as DENV protease inhibitors. Unfortunately, none of them have resulted in a clinically approved drug. Considering all the abovementioned facts, this review descriptively explains the molecular mechanism and therapeutic potential of DENV protease along with an up to date information on various competitive inhibitors reported against DENV protease. This review might be helpful for the researchers working in this area to understand the critical aspects of DENV protease that will help them develop effective and novel inhibitors against DENV to protect lives of millions of people worldwide.