Current Medicinal Chemistry - Volume 29, Issue 1, 2022

The aim of this review article is to summarize the knowledge available to date on prophylaxis achievements in the frame of the fight against Coronaviruses. This work will give an overview of what is reported in the recent literature on vaccines (under investigation or already developed like BNT162b2, mRNA-1273, and ChAdOx1-S) effective against the most pathogenic Coronaviruses (SARS-CoV-1, MERS-CoV-1, and SARS-CoV-2), with of course particular attention paid to those under development or already in use to combat the current COVID-19 (CoronaVIrus Disease 19) pandemic. Our main objective is to make a contribution to the comprehension, even at a molecular level, of what is currently ready for anti-SARS-CoV-2 prophylactic intervention, as well as to provide the reader with an overall picture of the most innovative approaches for the development of vaccines that could be of general utility in the fight against the most pathogenic Coronaviruses.

Introduction: Thalidomide is an old well-known drug firstly used as morning sickness relief in pregnant women and then withdrawn from the market due to its severe side effects on fetal normal development. However, over the last few decades, the interest in this old drug has been renewed because of its efficacy in several important disorders as, for instance, multiple myeloma, breast cancer, and HIV-related diseases due to its antiangiogenic and immunomodulatory properties. Unfortunately, even in these cases, many after effects as deep vein thrombosis, peripheral neuropathy, constipation, somnolence, pyrexia, pain, and teratogenicity have been reported showing the requirement of careful and monitored use. For this reason, research efforts are geared toward the synthesis and optimization of new thalidomide analogues lacking in toxic effects, able to erase these limits and improve the pharmacological profile. Aims: This review aims to examine the state-of-the-art concerning the current studies on thalidomide and its analogues towards cancer diseases focusing the attention on the possible mechanisms of action involved and the lack of toxicity. Conclusion: In the light of the collected data, thalidomide analogues and their ongoing optimization could lead, in the future, to the realization of a promising therapeutic alternative for fighting cancer.

Ferroptosis, which is an iron-dependent, non-apoptotic cell death mechanism, has recently been proposed as a novel approach in cancer treatment. Bearing distinctive features and its exclusive mechanism have put forward the potential therapeutic benefit of triggering this newly discovered form of cell death. Numerous studies have indicated that apoptotic pathways are often deactivated in resistant cells, leading to a failure in therapy. Hence, alternative strategies to promote cell death are required. Mounting evidence suggests that drug-resistant cancer cells are particularly sensitive to ferroptosis. Given that cancer cells consume a higher amount of iron than healthy ones, ferroptosis not only stands as an excellent alternative to trigger cell death and reverse drug-resistance, but also provides selectivity in therapy. This review focuses specifically on overcoming drugresistance in cancer through activating ferroptotic pathways and brings together the relevant chemotherapeutics-based and nanotherapeutics-based studies to offer a perspective for researchers regarding the potential use of this mechanism in developing novel therapeutic strategies.

ELAV-like protein 1 or HuR (human antigen R) is an RNA-binding protein that in humans is encoded by the ELAVL1 gene, and one of its best functions is to stabilize mRNAs in order to regulate gene expression. HuR protein overexpression has undoubtedly been linked to an increased risk of tumor growth, progression and metastasis, rendering it a potential therapeutic target candidate in cancer. Novel agents, interfering with HuR expression, have been tested, both in vitro and in vivo, with promising results. The aim of this paper is to review the existing literature regarding the potential agents that could actively act on and inhibit HuR expression. HuR molecule controls the expression of various proto-oncogenes, cytokines and growth factors, representing a major player in tumor progression, invasion and metastasis and constituting an emerging target for cancer therapy. PubMed database was thoroughly searched, and all published articles providing scientific data on molecules that can exhibit antitumorigenic effects via HuR inhibition were included. According to these data, HuR inhibition should be a promising target in cancer therapeutics.

There has been substantial progress in artificial intelligence (AI) algorithms and their medical sciences applications in the last two decades. AI-assisted programs have already been established for remote health monitoring using sensors and smartphones. A variety of AI-based prediction models are available for gastrointestinal, inflammatory, non-malignant diseases, and bowel bleeding using wireless capsule endoscopy, hepatitis-associated fibrosis using electronic medical records, and pancreatic carcinoma utilizing endoscopic ultrasounds. AI-based models may be of immense help for healthcare professionals in the identification, analysis, and decision support using endoscopic images to establish prognosis and risk assessment of patients’ treatment employing multiple factors. Enough randomized clinical trials are warranted to establish the efficacy of AI-algorithms assisted and non-AI-based treatments before approval of such techniques from medical regulatory authorities. In this article, available AI approaches and AI-based prediction models for detecting gastrointestinal, hepatic, and pancreatic diseases are reviewed. The limitations of AI techniques in such diseases’ prognosis, risk assessment, and decision support are discussed.

Tuberculosis (TB), induced by Mycobacterium tuberculosis (MTB), is a fatal infectious disease that kills millions of lives worldwide. The emergence of drug-resistant and multidrug-resistant cases is regarded as one of the most challenging threats to TB control due to the low cure rate. Therefore, TB and drug-resistant TB epidemic urge us to explore more effective therapies. The increasing knowledge of nanotechnology has extended the use of some nanomedicines for disease treatment in clinics, which also provide novel possibilities for nano-based medicines for TB treatment. Zinc oxide nanoparticles (ZnO NPs) have gained increasing attention for anti-bacterial uses based on their strong ability to induce reactive oxidative species (ROS) and release bactericidal Zinc ions (Zn2+), which are expected to act as novel strategies for TB and drug-resistant TB treatment. Some plant extracts, always from active herbal medicines, have been widely reported to show attractive anti-bacterial activity for infectious treatment, including TB. Here, we summarize the synthesis of ZnO NPs using plant extracts (green synthesized ZnO NPs), and further discuss their potentials for anti-TB treatments. This is the first review article discussing the anti-TB activity of ZnO NPs produced using plant extracts, which might contribute to the further applications of green synthesized ZnO NPs for anti-TB and drugresistant TB treatment

The essential amino acid tryptophan (Trp) undergoes catabolism through several pathways, producing biologically active metabolites that significantly impact physiological processes. The metabolic pathway responsible for the majority of Trp catabolism is the kynurenine synthesis pathway (KP). Serotonin and melatonin are among the most essential Trp pathways degradation products. It has emerged that a strong relationship exists between alterations in Trp metabolism and the onset and progression of atherosclerosis and diabetes. Atherosclerosis is a chronic inflammatory disease of the small and medium arteries wall caused by maladaptive local immune responses, which underpins several cardiovascular diseases (CVD). Systemic low-grade immune-mediated inflammation is implicated in atherosclerosis where pro-inflammatory cytokines, such as interferon-γ (IFN-γ), play a significant role. IFN-γ upregulates the enzyme indoleamine 2,3-dioxygenase (IDO), decreasing serum levels of the Trp and increasing metabolite levels of kynurenine. Increased IDO expression and activity could accelerate the atherosclerosis process. Therefore, activated IDO inhibition could offer possible treatment options regarding atherosclerosis management. Diabetes is a chronic metabolic disease characterized by hyperglycemia that, over time, leads to severe damage to the heart, blood vessels, eyes, kidneys, and peripheral nerves. Trp serum levels and lower activity of IDO were higher in future type 2 diabetes (T2DM) patients. This article reviews recent findings on the link between mammalian Trp metabolism and its role in atherosclerosis and diabetes and outlines the intervention strategies.

Over decades of its identification, numerous past and ongoing research has focused on β- amyloid cleaving enzyme 1 (BACE1) therapeutic roles as a target in treating Alzheimer's disease (AD). Although the initial BACE1 inhibitors at phase-3 clinical trials tremendously reduced β -amyloidassociated plaques in patients with AD, the researchers eventually discontinued the tests for lack of potency. This discontinuation has resulted in limited drug development and discovery targeted at BACE1, despite the high demand for dementia and AD therapies. It is, therefore, imperative to describe the detailed underlying biological basis of the BACE1 therapeutic option in neurological diseases. Herein, we highlight BACE1 bioactivity, genetic properties, and role in neurodegenerative therapy. We review research contributions on BACE1 exosite-binding antibody and allosteric inhibitor development as AD therapies. The review also covers BACE1 biological function, the disease-associated mechanisms, and the enzyme conditions for amyloid precursor protein site splitting. Based on the present review, we suggest further studies on anti-BACE1 exosite antibodies and BACE1 allosteric inhibitors. Non-active site inhibition might be the way forward to BACE1 therapy in Alzheimer's neurological disorder.

Background: The pathophysiology of cardiac arrest (CA) involves over-activation of systemic inflammatory responses, relative adrenal insufficiency, and glycocalyx damage. Corticosteroids have beneficial effects in preventing the perturbation of the endothelial glycocalyx. Objectives: The aim of this systematic review was to determine the efficacy of glucocorticoids in patients with cardiac arrest. Methods: We searched PubMed, Scopus, ISI Web of Science, Google Scholar, and Cochrane central register for relevant clinical trials and cohort studies until September 2019. Results: We retrieved 7 peer-reviewed published studies for the systematic review. Two studies were clinical trials evaluating 147 patients, while five illustrated cohort design, evaluating 196,192 patients. In total, 196,339 patients were assessed. There was limited evidence and conflicting results to establish a correlation between glucocorticoids and the survival of patients suffering from cardiac arrest. However, the links between these medications and survival-to-admission, survival-to discharge, and 1-year survival rates were strong and consistent in observational studies. Conclusion: The clinical evidence regarding the efficacy and safety of glucocorticoids in CA is limited to observational studies with inconsistent methodology and few clinical trials with a small sample size. Nevertheless, it seems that glucocorticoid supplementation during and after cardiopulmonary resuscitation (CPR) may have beneficial effects in terms of survival-to-admission, survival to discharge, 1-year survival rates, and an improved return of spontaneous circulation (ROSC) rate, especially in patients with hemodynamic instability and cardiovascular diseases (i.e., refractory hemodynamic shock). Future studies with high-quality, large-scale, long-term intervention and precise baseline characteristics are needed to evaluate the exact effective dose, duration, and efficacy of glucocorticoids in CA.

Background: SARS-CoV-2, which emerged in Wuhan, China, is a new global threat that has killed millions of people and continues to do so. This pandemic has not only threatened human life but has also triggered economic downturns across the world. Researchers have made significant strides in discovering molecular insights into SARSCoV- 2 pathogenesis and developing vaccines, but there is still no successful cure for SARS-CoV-2 infected patients. Objective: The present study has proposed a drug-repositioning pipeline for the design and discovery of an effective fungal-derived bioactive metabolite as a drug candidate against SARS-CoV-2. Methods: Fungal derivative “Cordycepin” was selected for this study to investigate the inhibitory properties against RNA-dependent RNA polymerase (RdRp) (PDB ID: 6M71) of SARS-CoV-2. The pharmacological profile, intermolecular interactions, binding energy, and stability of the compound were determined utilizing cheminformatic approaches. Subsequently, molecular dynamic simulation was performed to better understand the binding mechanism of cordycepin to RdRp. Results: The pharmacological data and retrieved molecular dynamics simulations trajectories suggest excellent drug-likeliness and greater structural stability of cordycepin, while the catalytic residues (Asp760, Asp761), as well as other active site residues (Trp617, Asp618, Tyr619, Trp800, Glu811) of RdRp, showed better stability during the overall simulation span. Conclusion: Promising results of pharmacological investigation along with molecular simulations revealed that cordycepin exhibited strong inhibitory potential against SARSCoV- 2 polymerase enzyme (RdRp). Hence, cordycepin should be highly recommended to test in a laboratory to confirm its inhibitory potential against the SARS-CoV-2 polymerase enzyme (RdRp).