Current Medicinal Chemistry - Volume 29, Issue 10, 2022

Although vaccination against SARS-CoV-2 infection has been initiated, effective therapies for severe COVID-19 disease are still needed. A promising therapeutic strategy is using FDA-approved drugs that have the biological potential to interfere with or modify some of the viral proteins capable of changing the disease's course. Recent studies highlight that some clinically safe drugs can suppress the viral life cycle while potentially promoting an adequate host inflammatory/immune response by interfering with the disease's cysteine proteome.

Acquired immunodeficiency syndrome (AIDS) has been a chronic, life-threatening disease for a long time. Though, a broad range of antiretroviral drug regimens is applicable for the successful suppression of virus replication in human immunodeficiency virus type 1 (HIV-1) infected people. The mutation-induced drug resistance problems during the treatment of AIDS forced people to continuously look for new antiviral agents. HIV-1 integrase (IN) and reverse transcriptase associated ribonuclease (RT-RNase H), two pivotal enzymes in HIV-1 replication progress, have gained popularity as druggable targets for designing novel HIV-1 antiviral drugs. During the development of HIV-1 IN and/or RT-RNase H inhibitors, computer-aided drug design (CADD), including homology modeling, pharmacophore, docking, molecular dynamics (MD) simulation and binding free energy calculation, represent a significant tool to accelerate the discovery of new drug candidates and reduce costs in antiviral drug development. In this review, we summarized the recent advances in the design of single- and dual-target inhibitors against HIV-1 IN or/and RT-RNase H as well as the prediction of mutation-induced drug resistance based on computational methods. We highlighted the results of the reported literatures and proposed some perspectives on the design of novel and more effective antiviral drugs in the future.

Background: Long non-coding RNAs (lncRNA) have influenced numerous biology processes, which has provoked great interest. Not only that, LncRNA DUXAP8 mediates tumorigenesis by affecting the activity of miRNAs, signaling pathways, and oncogene. Methods: The functions of DUXAP8 have been summarized by reading relevant articles on PubMed. Results: lncRNA DUXAP8 acts as an oncogene in most tumors. The abnormal overexpression is associated with the proliferation, invasion, migration, and anti-autophagy of tumors. DUXAP8 exerts promotion on Akt / mTOR signaling pathway, facilitating the occurrence of tumors. Furthermore, DUXAP8 affects the activity of miRNAs and proteins, showing its significant potential as a therapeutic target in human cancers. Conclusion: LncRNA DUXAP8 has been identified as an indispensable therapeutic target of the tumors, providing clinical treatment plans.

Background: Currently, it has been recognized that High-Density Lipoprotein (HDL) functionality plays a much more essential role in protection from atherosclerosis than circulating HDLcholesterol (HDL-C) levels per se. Cholesterol efflux capacity (CEC) from macrophages to HDL has been shown to be a key metric of HDL functionality. Thus, quantitative assessment of CEC may be an important tool for the evaluation of HDL functionality, as improvement of HDL function may lead to a reduction of the risk for Cardiovascular disease (CVD). Introduction: Although the cardioprotective action of HDLs is exerted mainly through their involvement in the reverse cholesterol transport (RCT) pathway, HDLs have also important anti-inflammatory, antioxidant, antiaggregatory and anticoagulant properties that contribute to their favorable cardiovascular effects. Certain genetic, pathophysiologic, disease states and environmental conditions may influence the cardioprotective effects of HDL either by inducing modifications in lipidome and/or protein composition, or in the enzymes responsible for HDL metabolism. On the other hand, certain healthy habits or pharmacologic interventions may actually favorably affect HDL functionality. Methods: The present review discusses the effects of environmental factors, including obesity, smoking, alcohol consumption, dietary habits, various pharmacologic interventions, as well as aerobic exercise, on HDL functionality. Results: Experimental and clinical studies or pharmacological interventions support the impact of these environmental factors in the modification of HDL functionality, although the involved mechanisms are not fully understood. Conclusion: Further research should be conducted to identify the underlying mechanisms of these environmental factors and to identify new pharmacologic interventions capable of enhancing CEC, improving HDL functionality and potentially improving cardiovascular risk.

Background: The chick chorioallantoic membrane (CAM) model has attracted a great deal of interest in pharmaceutical and biological research as an alternative or complimentary in vivo assay to animal models. Traditionally, CAM assay has been widely used to perform some toxicological studies, specifically to evaluate the skin, ocular and embryo toxicity of new drugs and formulations, and to perform angiogenesis studies. Due to the possibility to generate the tumors onto the CAM, this model has also become an excellent strategy to evaluate the metastatic potential of different tumours and to test the efficacy of novel anticancer therapies in vivo. Moreover, in the recent years, its use has considerably grown in other research areas, including the evaluation of new anti-infective agents, the development of biodistribution studies and in tissue engineering research. Objective: This manuscript provides a critical overview of the use of CAM model in pharmaceutical and biological research, especially to test the toxicity of new drugs and formulations and the biodistribution and the efficacy of novel anticancer and antiinfective therapies, analyzing its advantages and disadvantages in comparison to animal models. Conclusion: The chick chorioallantoic membrane model shows a great utility in several research areas, such as cancer, toxicology, biodistribution studies and anti-infective therapies. In fact, it has become an intermediate stage between in vitro experiments and animal studies, and, in the case of toxicological studies (skin and ocular toxicity), it has even replaced the animal models.

Nicotinamide adenine dinucleotide (NAD+) is a key player in many metabolic pathways as an activated carrier of electrons. In addition to being the cofactor for redox reactions, NAD+ also serves as the substrate for various enzymatic transformations such as adenylation and ADP-ribosylation. Maintaining cellular NAD+ homeostasis has been suggested as an effective anti-aging strategy. Given the importance of NAD+ in regulating a broad spectrum of cellular events, small molecules targeting NAD+ metabolism have been pursued as therapeutic interventions for the treatment of mitochondrial disorders and agerelated diseases. In this article, small molecule regulators of NAD+ biosynthetic enzymes will be reviewed. The focus will be given to the discovery and development of these molecules, the mechanism of action as well as their therapeutic potentials.

High-throughput screening facilitates the rapid identification of novel hit compounds; however, it remains challenging to design effective high-throughput assays, partially due to the difficulty of achieving sensitivity in the assay techniques. Among the various analytical methods that are used, fluorescence-based assays dominate due to their high sensitivity and ease of operation. Recent advances in activity-based sensing/imaging have further expanded the availability of fluorescent probes as monitors for high-throughput screening of result outputs. In this study, we have reviewed various activity-based fluorescent probes used in high-throughput screening assays, with an emphasis on their structure-related working mechanisms. Moreover, we have explored the possibility of developing additional and better probes to boost hit identification and drug development against various targets.

Alzheimer’s disease (AD) is a complex neurological disorder and multiple pathological factors are believed to be involved in the genesis and progression of the disease. A number of hypothesis including Acetylcholinesterase, Monoamine oxidase, β- Amyloid, Tau protein etc. have been proposed for the initiation and progression of the disease. At present, acetylcholine esterase inhibitors and memantine (NMDAR antagonist) are the only approved therapy for the symptomatic management of AD. Most of these single-target drugs have miserably failed in the treatment or halting the progression of the disease. Multi-factorial diseases like AD require complex treatment strategies that involve simultaneous modulation of a network of interacting targets. Since last few years, Multi-Target-Directed Ligands (MTDLs) strategy, drugs that can simultaneously hit multiple targets, is being explored as an effective therapeutic approach for the treatment of AD. In the current review article, the authors have briefly described various pathogenic pathways associated with the AD. Importance of Multi-Target-Directed Ligands and their design strategies in recently reported articles have been discussed in detail. Potent leads identified through various structure-activity relationship studies and their drug like characteristics are described. Recently developed promising compounds have been summarized in the article. Some of these MTDLs with balanced activity profile against different targets have the potential to be developed as drug candidates for the treatment of AD.

Nanoparticles (NPs), due to their medical applications, are widely used. Accordingly, the use of mesenchymal stem cells is one of the most important alternatives in the tissue engineering field. NPs play effective roles in stem cells proliferation and differentiation. The combination of NPs and tissue regeneration by stem cells has created a new therapeutic approach towards humanity. Of note, the physicochemical properties of NPs determine their biological function. Interestingly, various mechanisms such as modulation of signaling pathways and generation of reactive oxygen species, are involved in NPs-induced cellular proliferation and differentiation. This review summarized the types of nanomaterials effective on stem cell differentiation, the physicochemical features, biomedical application of these materials and the relationship between nanomaterials and environment.