Structure-based inhibitor design and repurposing clinical drugs to target SARS-CoV-2 proteases

SARS-CoV-2, the coronavirus responsible for the current COVID-19 pandemic, encodes two proteases, 3CLpro and PLpro, two of the main antiviral research targets. Here we provide an overview of the structures and functions of 3CLpro and PLpro and examine strategies of structure-based drug designing and drug repurposing against these proteases. Rational structure-based drug design enables the generation of potent and target-specific antivirals. Drug repurposing offers an attractive prospect with an accelerated turnaround. Thus far, several protease inhibitors have been identified, and some candidates are undergoing trials that may well prove to be effective antivirals against SARS-CoV-2.

Synthesis of trans N-Substituted Pyrrolidine Derivatives Bearing 1,2,4-triazole Ring

Background: 1,2,4-triazoles scaffolds display significant biological activities due to hydrogen bonding, solubility, dipole character, and rigidity Objective: The core motif of 1,2,4-triazoles plays a vital role in clinical drugs such as Rizatriptan (anti-migraine), Ribavirin (antiviral), anastrozole (anticancer), etizolam (anxiolytic), estazolam (anticonvulsant), alprazolam (anti-hypnotic), letrozole (aromatase inhibitor), loreclezole (anticonvulsant), trazadone (antidepressant) etc Method: Epoxide ring opening of tert-butyl 6-oxa-3-azabicyclo [3.1.0] hexane-3-carboxylate followed by methylation under basic conditions and de-protection gave the corresponding trans 1-(4-methoxypyrrolidin-3-yl)-1H-1,2,4-triazole hydrochloride salt as the precursor. This precursor on reaction with substituted benzoyl chlorides and benzyl bromides gave the desired amide and amine products Results: A library of 14 N-substituted pyrrolidine derivatives i.e. trans3-methoxy-4-(1H-1,2,4-triazol-1-yl) pyrrolidin-1-yl) (phenyl)methanone and trans 1-benzyl-4-methoxypyrrolidin-3-yl)-1H-1,2,4-triazole were prepared Conclusion: Eight novel amides (6a-h) and six amines (8a-f) derivatives were synthesized using 1-(4-methoxypyrrolidin-3-yl)-1H-1,2,4-triazole 4 salt with substituted benzoyl chlorides and benzyl bromides.

Metal Complexes or Chelators with ROS Regulation Capacity: Promising Candidates for Cancer Treatment

Reactive oxygen species (ROS) are rapidly eliminated and reproduced in organisms, and they always play important roles in various biological functions and abnormal pathological processes. Evaluated ROS have frequently been observed in various cancers to activate multiple pro-tumorigenic signaling pathways and induce the survival and proliferation of cancer cells. Hydrogen peroxide (H2O2) and superoxide anion (O2•−) are the most important redox signaling agents in cancer cells, the homeostasis of which is maintained by dozens of growth factors, cytokines, and antioxidant enzymes. Therefore, antioxidant enzymes tend to have higher activity levels to maintain the homeostasis of ROS in cancer cells. Effective intervention in the ROS homeostasis of cancer cells by chelating agents or metal complexes has already developed into an important anti-cancer strategy. We can inhibit the activity of antioxidant enzymes using chelators or metal complexes; on the other hand, we can also use metal complexes to directly regulate the level of ROS in cancer cells via mitochondria. In this review, metal complexes or chelators with ROS regulation capacity and with anti-cancer applications are collectively and comprehensively analyzed, which is beneficial for the development of the next generation of inorganic anti-cancer drugs based on ROS regulation. We expect that this review will provide a new perspective to develop novel inorganic reagents for killing cancer cells and, further, as candidates or clinical drugs.

Natural Indole Alkaloids from Marine Fungi: Chemical Diversity and Biological Activities

The indole scaffold is one of the most important heterocyclic ring systems for pharmaceutical development, and serves as an active moiety in several clinical drugs. Fungi derived from marine origin are more liable to produce novel indole-containing natural products due to their extreme living environments. The indole alkaloids from marine fungi have drawn considerable attention for their unique chemical structures and significant biological activities. This review attempts to provide a summary of the structural diversity of marine fungal indole alkaloids including prenylated indoles, diketopiperazine indoles, bisindoles or trisindoles, quinazoline-containing indoles, indole-diterpenoids, and other indoles, as well as their known biological activities, mainly focusing on cytotoxic, kinase inhibitory, antiinflammatory, antimicrobial, anti-insecticidal, and brine shrimp lethal effects. A total of 306 indole alkaloids from marine fungi have been summarized, covering the references published from 1995 to early 2021, expecting to be beneficial for drug discovery in the future.

Recent Progress in Lymphangioma

Lymphangioma is a common type of congenital vascular disease in children with a broad spectrum of clinical manifestations. The current classification of lymphangioma by International Society for the Study of Vascular Anomalies is largely based on the clinical manifestations and complications and is not sufficient for selection of therapeutic strategies and prognosis prediction. The clinical management and outcome of lymphangioma largely depend on the clinical classification and the location of the disease, ranging from spontaneous regression with no treatment to severe sequelae even with comprehensive treatment. Recently, rapid progression has been made toward elucidating the molecular pathology of lymphangioma and the development of treatments. Several signaling pathways have been revealed to be involved in the progression and development of lymphangioma, and specific inhibitors targeting these pathways have been investigated for clinical applications and clinical trials. Some drugs already currently in clinical use for other diseases were found to be effective for lymphangioma, although the mechanisms underlying the anti-tumor effects remain unclear. Molecular classification based on molecular pathology and investigation of the molecular mechanisms of current clinical drugs is the next step toward developing more effective individualized treatment of children with lymphangioma with reduced side effects.

Mechanism of drug-induced liver injury and hepatoprotective effects of natural drugs

Drug-induced liver injury (DILI) is a common adverse drug reaction (ADR) and a serious threat to health that affects disease treatments. At present, no targeted clinical drugs are available for DILI. Traditional natural medicines have been widely used as health products. Some natural medicines exert specific hepatoprotective effects, with few side effects and significant clinical efficacy. Thus, natural medicines may be a promising direction for DILI treatment. In this review, we summarize the current knowledge, common drugs and mechanisms of DILI, as well as the clinical trials of natural drugs and their bioactive components in anticipation of the future development of potential hepatoprotective drugs.

Revisiting CYP2C9-Mediated drug-drug Interactions: A Review

Drug-drug interactions (DDI) are the most common cases that occur in our healthcare in which are very alarming as it may lead to severe complications. Consumption of natural products concomitantly with conventional drugs or treatment using polypharmacy have become the norm that promoting the potential of pharmacokinetic or pharmacodynamic drug interactions as the combination may mimic, increase or reduce the effects of the drug or the herb which could result in clinically significant interactions. CYP2C9 is the second major isoform from CYP450 family of enzyme, which responsible in phase 1 metabolism of 15-20% clinical drugs. Up to date, many substrates of CYP2C9 have been discovered and these discoveries may open more doors for potential drug-drug interactions in patients. Many studies have been done to evaluate the effect of drugs on the activity of CYP2C9 and how it influenced the effectiveness of therapy in patients. Various data regarding CYP2C9 related DDI from in vitro, in vivo and clinical studies were critically discussed in this review to provide insights on how these drugs and natural products may exhibit drug interactions clinically. This review could be beneficial reference material for health practitioners and researchers.

Research Progress on the Neuroprotective Effect of Leonurine on Ischemic Stroke

Leonurus is one of the commonly used clinical drugs in traditional Chinese medicine. In recent years, leonurus has been widely used for cerebrovascular diseases. With the deepening of research, the effect of its main component, leonurine, on the central nervous system has become clearer, and its mechanism has been confirmed and explained from many aspects. For reference, this paper discusses the latest research on the neuroprotective effect of leonurine on ischemic stroke at home and abroad in recent years.

Cytochrome P450 Enzymes and Drug Metabolism in Humans

Human cytochrome P450 (CYP) enzymes, as membrane-bound hemoproteins, play important roles in the detoxification of drugs, cellular metabolism, and homeostasis. In humans, almost 80% of oxidative metabolism and approximately 50% of the overall elimination of common clinical drugs can be attributed to one or more of the various CYPs, from the CYP families 1–3. In addition to the basic metabolic effects for elimination, CYPs are also capable of affecting drug responses by influencing drug action, safety, bioavailability, and drug resistance through metabolism, in both metabolic organs and local sites of action. Structures of CYPs have recently provided new insights into both understanding the mechanisms of drug metabolism and exploiting CYPs as drug targets. Genetic polymorphisms and epigenetic changes in CYP genes and environmental factors may be responsible for interethnic and interindividual variations in the therapeutic efficacy of drugs. In this review, we summarize and highlight the structural knowledge about CYPs and the major CYPs in drug metabolism. Additionally, genetic and epigenetic factors, as well as several intrinsic and extrinsic factors that contribute to interindividual variation in drug response are also reviewed, to reveal the multifarious and important roles of CYP-mediated metabolism and elimination in drug therapy.