Natural Inhibitors Research Articles

Identification of potential natural product inhibitors against the Mpro enzyme of Covid-19: a computational study

Identification of potential natural product inhibitors against the Mpro enzyme of Covid-19: a computational study

Elevated glucose levels increase vascular calcification risk by disrupting extracellular pyrophosphate metabolism.

Vascular calcification is a major contributor to cardiovascular disease, especially diabetes, where it exacerbates morbidity and mortality. Although pyrophosphate is a recognized natural inhibitor of vascular calcification, there have been no prior studies examining its specific deficiency in diabetic conditions. This study is the first to analyze the direct link between elevated glucose levels and disruptions in extracellular pyrophosphate metabolism. Rat aortic smooth muscle cells, streptozotocin (STZ)-induced diabetic rats, and diabetic human aortic smooth muscle cells were used to assess the effects of elevated glucose levels on pyrophosphate metabolism and vascular calcification. The techniques used include extracellular pyrophosphate metabolism assays, thin-layer chromatography, phosphate-induced calcification assays, BrdU incorporation for DNA synthesis, aortic smooth muscle cell viability and proliferation assays, and quantitative PCR for enzyme expression analysis. Additionally, extracellular pyrophosphate metabolism was examined through the use of radiolabeled isotopes to track ATP and pyrophosphate transformations. Elevated glucose led to a significant reduction in extracellular pyrophosphate across all diabetic models. This metabolic disruption was marked by notable downregulation of both the expression and activity of ectonucleotide pyrophosphatase/phosphodiesterase 1, a key enzyme that converts ATP to pyrophosphate. We also observed an upregulation of ectonucleoside triphosphate diphosphohydrolase 1, which preferentially hydrolyzes ATP to inorganic phosphate rather than pyrophosphate. Moreover, tissue-nonspecific alkaline phosphatase activity was markedly elevated across all diabetic models. This shift in enzyme activity significantly reduced the pyrophosphate/phosphate ratio. In addition, we noted a marked downregulation of matrix Gla protein, another inhibitor of vascular calcification. The impaired pyrophosphate metabolism was further corroborated by calcification experiments across all three diabetic models, which demonstrated an increased propensity for vascular calcification. This study demonstrated that diabetes-induced high glucose disrupts extracellular pyrophosphate metabolism, compromising its protective role against vascular calcification. These findings identify pyrophosphate deficiency as a potential mechanism in diabetic vascular calcification, highlighting a new therapeutic target. Strategies aimed at restoring or enhancing pyrophosphate levels may offer significant potential in mitigating cardiovascular complications in diabetic patients, meriting further investigation.

Unlocking Neuraminidase Inhibitors: Insights from Natural Products through Pharmacophore Modeling, Virtual Screening, and Molecular Docking

Background: Neuraminidase enzyme plays a major role in the life cycle of influenza viruses. Targeting neuraminidases is a key strategy in preventing and treating influenza A and B spread by inhibiting the release of new viral particles from infected cells. Developing new neuraminidase inhibitors with enhanced efficacy and reduced risk of resistance is the ultimate of ongoing research. Objective: In this study, we tried to shed light on molecules of natural origin that inhibit neuraminidase enzyme by utilizing different aspects of in silico studies. Methods: The work started by generating structure-based pharmacophore, later used for the virtual screening of electronic libraries constructed from chemical and natural compounds. Hits raised from virtual screening were subjected to molecular docking to assess and explain different modes of interactions with the neuraminidase enzyme. Drug likeness and ADME filters were applied to choose compounds that may be taken effectively by oral route with good gastrointestinal absorption and acceptable pharmacokinetics with respect to Lipinski and Ghose rules. The hits were also inspected for toxicity risks, including mutagenic, tumorigenic, irritant, and reproductive effects. Results: 7 features of the generated pharmacophore from the potent inhibitor Oselatamiver were the base for virtual screening. The results obtained by database screening highlighted 4 natural compounds listed in the COCONUT library (CNP 0125691 (Penicitrinol K), CNP0256196 (Frenolicin D), CNP 0138184, and CNP 0206296) as potential neuraminidase inhibitors. The compounds showed a similar interaction profile to Oseltamivir by molecular docking with high binding affinity. The key residue TYR 406 hydrogen bonded to Penicitrinol and Frenolicin D as well as to Oseltamevir. The 4 natural compounds exerted drug-like properties and promising pharmacokinetic characters. Toxicity risks estimations put Penicitrinol K and Frenolicin as devoted to mutagenic, tumorigenic, irritant and reproductive potentials. Penicitrinol K and Frenolicin are assigned for further in vitro and in vivo studies as promising neuraminidase inhibitors. Conclusion: Penicitrinol K, and Frenolicin D are promising natural neuraminidase inhibitors, exhibiting favourable drug-like properties and low toxicity risks in addition to showing the pattern of interaction profiles with neuraminidase enzymes similar to the known drug Oseltamivir contributing to the development of effective antiviral therapies against influenza, suggesting further in vitro and in vivo evaluation.

Synthesis of long-chain polyester polymers and their properties as crude oil pour point depressant.

Using acrylic acid advanced ester and styrene as raw materials, the long-chain polyester polymer, polyacrylic acid advanced ester-styrene pour point depressant (P-PPD), was synthesized by molecular design, and its structure was characterized by infrared spectroscopy and nuclear magnetic resonance. In addition, this study experimentally investigated the effect of P-PPD on the phase equilibrium and induction time of natural gas hydrate inhibitors in deionized water (DW) and crude oil/water (O/W) systems, respectively. Polyvinylpyrrolidone (PVP) and mono ethylene glycol (EG) were selected as representatives of kinetic hydrate inhibitor (KHIs) and thermodynamic hydrate inhibitor (THIs), respectively. The results exhibit that P-PPD played a sight role in the phase equilibrium of hydrate, while the addition of P-PPD significantly prolonged the induction time of methane hydrate both in O/W + PVP, OW + EG and O/W + PVP + EG system, indicating that the addition of as-synthesized PPD has a synergistic inhibition effect on the nucleation ability of methane hydrate and can prevent hydrate from formatting during oil and gas transport process, and thus guarantee the flow assurance. The findings of this work will provide a data reference for the hybrid use of hydrate inhibitors and pour point depressants in oil and gas transport.

Targeting N-methyl-lysine histone demethylase KDM4 in cancer: natural products inhibitors as a driving force for epigenetic drug discovery.

KDM4A-F enzymes are a subfamily of histone demethylases containing the Jumonji C domain (JmjC) using Fe(II) and 2-oxoglutarate for their catalytic function. KDM4 enzymes are overexpressed or deregulated in cancer, thus leading to alteration in chromatin structure and transcriptional defects. As KDM4 enzymes have been associated with malignancy, they may represent novel targets for developing innovative therapeutic tools to treat different solid and blood tumors, of note, KDM4A is the isozyme most frequently associated with aggressive phenotypes of these tumors. To this aim, industrial and academic medicinal chemistry efforts have identified different KDM4 inhibitors. In most cases, these are pan-KDM4 inhibitors, with low selectivity against other Jumonji family members. The pharmacophoric features of the inhibitors frequently include a chelating group capable of coordinating the catalytic iron within the active site of the KDM4 enzyme. Nonetheless, non-chelating compounds have also demonstrated promising inhibitory activity, suggesting potential flexibility in the drug design. Several natural products, containing monovalent or bivalent chelators, have been identified as KDM4 inhibitors, albeit with a micromolar inhibition potency. This highlights the potential for leveraging them as templates for the design and synthesis of new derivatives, exploiting nature's chemical diversity to pursue more potent and selective KDM4 inhibitors.

Resveratrol Inhibits Nucleosome Binding and Catalytic Activity of PARP1

The natural polyphenol resveratrol is a biologically active compound that interacts with DNA and affects the activity of some nuclear enzymes. Its effect on the interaction between nucleosomes and poly(ADP-ribose) polymerase-1 (PARP1) and on the catalytic activity of PARP1 was studied using Western blotting, spectrophotometry, electrophoretic mobility shift assay, and single particle Förster resonance energy transfer microscopy. Resveratrol inhibited PARP1 activity at micro- and sub-micromolar concentrations, but the inhibitory effect decreased at higher concentrations due to the aggregation of the polyphenol. The inhibition of PARP1 by resveratrol was accompanied by its binding to the enzyme catalytic center and a subsequent decrease in PARP1 affinity to nucleosomal DNA. Concurrent binding of talazoparib to the substrate binding pocket of PARP1, which occurs in the presence of resveratrol, restores the interaction of PARP1 with nucleosomes, suggesting that the binding sites of resveratrol and talazoparib overlap. The data suggest that resveratrol can be classified as a natural inhibitor of PARP1.

Berberine: A Multi-Target Natural PCSK9 Inhibitor with the Potential to Treat Diabetes, Alzheimer's, Cancer and Cardiovascular Disease.

Berberine is a natural product with a wide range of pharmacological effects. It has antimicrobial, anti-cancer, anti-inflammatory, anti-hyperlipidemic, neuroprotective, and cholesterollowering properties, among others. It has been used in traditional Chinese and Ayurvedic medicine for 3000 years and is generally well-tolerated with few side effects. Its main drawback is low oral bioavailability, which has hindered widespread clinical use. However, recent interest has surged with the emergence of evidence that berberine is effective in treating cancer, diabetes, Alzheimer's disease, and cardiovascular disease via multiple mechanisms. It enhances insulin sensitivity and secretion by pancreatic β-cells in Type 2 Diabetes Mellitus in addition to reducing pro-inflammatory cytokines such as IL-6, IL-1β, TLR4 and TNF-α. These cytokines are elevated in Alzheimer's disease, cardiovascular disease, and diabetes. Reductions in pro-inflammatory cytokine levels are associated with positive outcomes such as improved cognition, reduced cardiovascular events, and improved glucose metabolism and insulin sensitivity. Berberine is a natural PCSK9 inhibitor, which contributes to its hypolipidemic effects. It also increases low-density lipoprotein receptor expression, reduces intestinal cholesterol absorption, and promotes cholesterol excretion from the liver to the bile. This translates into a notable decrease in LDL cholesterol levels. High LDL cholesterol levels are associated with increased cardiovascular disease risk. Novel synthetic berberine derivatives are currently being developed that optimize LDL reduction, bioavailability, and other pharmacokinetic properties.

Computational Advancement towards the Identification of Natural Inhibitors for Dengue Virus: A Brief Review.

Viral infectious illnesses represent a severe hazard to human health due to their widespread incidence worldwide. Among these ailments, the dengue virus (DENV) infection stands out. World Health Organization (WHO) estimates that DENV infection affects ~400 million people each year, with potentially fatal symptoms showing up in 1% of the cases. In several instances, academic and pharmaceutical researchers have conducted several pilot and clinical studies on a variety of topics, including viral epidemiology, structure and function analyses, infection source and route, therapeutic targets, vaccinations, and therapeutic drugs. Amongst Takeda, TAK-003, Sanofi, Dengvaxia®, and Butantan/NIH/Merck, Dengvaxia® (CYD-TDV) is the only licensed vaccination yet; however, the potential inhibitors are under development. The biology and evolution of DENVs are briefly discussed in this review, which also compiles the most recent studies on prospective antiviral targets and antiviral candidates. In conclusion, the triumphs and failures have influenced the development of anti-DENV medications, and the findings in this review article will stimulate more investigation.

Structural and biochemical insights into the mechanism of the anti-CRISPR protein AcrIE3.

Anti-CRISPR (Acr) proteins are natural inhibitors of CRISPR-Cas systems, found in bacteriophages and other genetic elements. AcrIE3, identified in a Pseudomonas phage, inactivates the type I-E CRISPR-Cas system in Pseudomonas aeruginosa by engaging with the Cascade complex. However, its precise inhibition mechanism has remained elusive. In this study, we present a comprehensive structural and biochemical analysis of AcrIE3, providing mechanistic insight into its anti-CRISPR function. Our results reveal that AcrIE3 selectively binds to the Cas8e subunit of the Cascade complex. The crystal structure of AcrIE3 exhibits an all-helical fold with a negatively charged surface. Through extensive mutational analyses, we show that AcrIE3 interacts with the protospacer adjacent motif (PAM) recognition site in Cas8e through its negatively charged surface residues. These findings enhance our understanding of the structure and function of type I-E Acr proteins, suggesting PAM interaction sites as primary targets for divergent Acr inhibitors.

Natural Inhibitors of the Polyphenol Oxidase Activity Isolated from Shredded Stored Iceberg Lettuce (Lactuca sativa L.)

Polyphenol oxidase (PPO) is the key enzyme responsible for enzymatic browning. To extend the shelf life of shredded lettuce, knowledge about biochemical PPO properties is required. The characterization of the enzyme from shredded, cold-stored lettuce was performed using pyrocatechol and the endogenous substrate (ES) (lettuce phenolics). The optimum pH and temperature for PPO activity were 5 and 50 °C, respectively. Natural infusions used as the PPO inhibitors (IC50) were ranked as follows: lovage (0.09%), marjoram (0.13%), orange peel (0.14%), oregano (0.15%), basil (0.22%), lemon peel (0.24%), parsley leaves (0.58%), and wheat bran (1.06%). Among well-recognized PPO inhibitors, kojic acid (0.00043%), ascorbic acid (0.00053%), and L-cysteine (0.00085%) were the most effective. Among the metal ions, MgCl2, FeCl2, and CaCl2 at 0.5 mM inhibited the PPO activity most effectively (by 28%, 27%, and 21%, respectively). The substrate used (pyrocatechol/ES) significantly influenced the enzyme inhibition. Using pyrocatechol, the lovage extract acted in a mixed mode (Kmi = 27.8 mM, Vmaxi = 2.03 mU), while the ES acted according to the non-competitive mode (Kmi= 0.57 mg GAE/mL, Vmax = 0.0046 U). The study confirms that natural extracts are more effective than L-cysteine when the ES is used. A pre-storage treatment with an infusion may be potentially used to improve the quality of shredded lettuce.

Efflux Pump Inhibitors as a Broad-Spectrum Strategy to Combat Multidrug Resistance Acenitobacter Baumanii

The World Health Organization (WHO) identifies A. baumannii as one of the most resistant pathogens. Over the past few years, there has been a significant rise in its resistance to a wide array of antibiotics. Multidrug resistance is attributed to several mechanisms, with efflux pumps being the most notable. Recently, the development of new treatment strategies to tackle A. baumannii infections has shown great promise. This review focuses on the various families of efflux pumps in A. baumannii and explores innovative therapeutic options that have emerged over the past four years. Specifically, we emphasize synthetic and natural efflux pump inhibitors (EPIs), nanoparticles, bacteriophage therapy, and antimicrobial peptides (AMPs) as part of these novel strategies.

An In Silico Approach to Discover Efficient Natural Inhibitors to Tie Up Epstein–Barr Virus Infection

Epstein–Barr virus (EBV), also known as human herpesvirus 4, is a member of the herpes virus family. EBV is a widespread virus and causes infectious mononucleosis, which manifests with symptoms such as fever, fatigue, lymphadenopathy, splenomegaly, and hepatomegaly. Additionally, EBV is associated with different lymphocyte-associated non-malignant, premalignant, and malignant diseases. So far, no effective treatment or therapeutic drug is known for EBV-induced infections and diseases. This study investigated natural compounds that inhibit EBV glycoprotein L (gL) and block EBV fusion in host cells. We utilised computational approaches, including molecular docking, in silico ADMET analysis, and molecular dynamics simulation. We docked 628 natural compounds against gL and identified the four best compounds based on binding scores and pharmacokinetic properties. These four compounds, with PubChem CIDs 4835509 (CHx-HHPD-Ac), 2870247 (Cyh-GlcNAc), 21206004 (Hep-HHPD-Ac), and 51066638 (Und-GlcNAc), showed several interactions with EBV gL. However, molecular dynamics simulations indicated that the protein–ligand complexes of CID: 4835509 (CHx-HHPD-Ac) and CID: 2870247 (Cyh-GlcNAc) are more stable than those of the other two compounds. Therefore, CIDs 4835509 and 2870247 (Cyh-GlcNAc) may be potent natural inhibitors of EBV infection. These findings can open a new way for effective drug design against EBV and its associated infections and diseases.

Effect of Natural Inhibitors on the Corrosion Properties of Grade 2 Titanium Alloy.

This study investigates the effects of natural inhibitors (pomegranate, algae, and tomato extracts) on the corrosion resistance of titanium (grade 2). To deepen understanding the inhibition mechanism, Molecular Dynamic (MD) and Monte Carlo (MC) simulations were employed to analyze adsorption behaviors and identify optimal adsorption sites on titanium oxide (TiO2) surfaces for compounds within the inhibitors. Results indicate non-flat adsorption orientations, with pomegranate peel extract components showing superior inhibition capabilities, attributed to the formation of strong O-H chemical bonds with the TiO2 surface. In the experimental part of the study Electrochemical Impedance Spectroscopy (EIS) and Potentiodynamic Polarization (PDP) were conducted. Two electrolytes were tested: a solution 3.5% NaCl and a solution 0.5 M NaOH. All the tests were performed with 5% of inhibitor and with the reference solution. Also, inhibition efficiency was calculated on the base of PDP tests. The study found that pomegranate extract can act as a good corrosion inhibitor for titanium alloy in aqueous solutions 0.5 M NaOH. This was demonstrated by the increase in the corrosion potential and impedance modulus and decrease in the corrosion current density after the addition of pomegranate extract to the solution. However, in a 3.5% NaCl solution, the efficacy of pomegranate extract was less pronounced, probably due to the high aggressivity of the electrolyte. Tomato and algae extract have instead shown very low inhibition effects in all the tested conditions.

Prolonging the circulatory half-life of C1 esterase inhibitor via albumin fusion.

Hereditary Angioedema (HAE) is an autosomal dominant disease characterized by episodic swelling, arising from genetic deficiency in C1-esterase inhibitor (C1INH), a regulator of several proteases including activated Plasma kallikrein (Pka). Many existing C1INH treatments exhibit short circulatory half-lives, precluding prophylactic use. Hexahistidine-tagged truncated C1INH (trC1INH lacking residues 1-97) with Mutated N-linked Glycosylation Sites N216Q/N231Q/N330Q (H6-trC1INH(MGS)), its murine serum albumin (MSA) fusion variant (H6-trC1INH(MGS)-MSA), and H6-MSA were expressed in Pichia pastoris and purified via nickel-chelate chromatography. Following intravenous injection in mice, the mean terminal half-life of H6-trC1INH(MGS)-MSA was significantly increased versus that of H6-trC1INH(MGS), by 3-fold, while remaining ~35% less than that of H6-MSA. The extended half-life was achieved with minimal, but significant, reduction in the mean second order rate constant of Pka inhibition of H6-trC1INH(MGS)-MSA by 33% relative to that of H6-trC1INH(MGS). Our results validate albumin fusion as a viable strategy for half-life extension of a natural inhibitor and suggest that H6-trC1INH(MGS)-MSA is worthy of investigation in a murine model of HAE.

Efficacy of natural and synthetic inhibitors in the elimination of viruses in potato (Solanum tuberosum L.)

Background. Developing new effective plant protection methods against viruses is a vital task for seed potato production. The use of virus inhibitors (mainly synthetic ones) is the most common method in potato virus control. Products of natural origin might be a way to reduce the dependence on synthetic inhibitors. Among the former, extracts from seaweeds have high potential, producing a low or no negative impact on the environment or human health. Materials and methods. The materials of the research included potato cvs. ‘Poseidon’ and ‘Orion’ developed at the Federal Scientific Center of Agricultural Biotechnology of the Far East named after A.K. Chaika, the commercial antiviral product Ribavirin, and the sulfated polysaccharide – carrageenan – obtained from red algae at the G.B. Elyakov Pacific Institute of Bioorganic Chemistry. A highly sensitive PCR method was employed to detect viral infections in plant samples. Results. The efficacy of chemotherapy with Ribavirin (0.03%) was established at 79.8% against PVY, 77.0% against PLRV, 80.3% against PVM, and 84.5% against PVS. The most successfully eliminated viruses were PVY, PVM, and PVS. Carrageenan as an antiviral substance eliminated potato viruses at the following rates: PLRV in 74.7% of the explants, PVM in 70.2%, PVS in 69.2%, and PVY in 16.9%. Conclusion. Analyzing the antiviral activity of natural and synthetic virus inhibitors in the case study of carrageenan and Ribavirin demonstrated their high efficacy against potato viruses. Natural polysaccharides – carrageenans – were observed to have a significant antiviral effect, so their use in agricultural biotechnology might be promising for new experiments. Our approach successfully eliminated viruses in two new promising potato cultivars, ‘Poseidon’ and ‘Orion’, which were included in the system of virus-free seed production. These cultivars were submitted for patenting and official testing under the State Variety Trials.

Virtual Screening of Apigenin and Luteolin as Natural Aromatase Inhibitors for the Treatment of Breast Cancer Patients

Aromatase is an enzyme that converts androgens (like testosterone) to estrogens (like 17- estradiol). It is also a highly successful therapeutic target for endocrine-responsive breast cancer. Aromatase inhibitors, which suppress estrogen synthesis in postmenopausal women, have been useful in the treatment of individuals with estrogen receptor-positive breast cancer. Anastrozole is an aromatase inhibitor medication that is used in the management and treatment of breast cancer. Flavonoids inhibit cancer cell proliferation by causing apoptosis, encouraging autophagy, and changing the cell cycle. Although several dietary flavonoids (like in parsley, celery and Broccoli) can inhibit aromatase, the tissue specificity and mechanism of binding are uncertain. According to several researches, flavonoids (apigenin and luteolin) dramatically suppress estrogen production. The study aims to examine binding of 3EQM (Aromatase) in the A chain with both of flavonoid (Apigenin and luteolin) and Anastrozole, using an in silico approach. PyRx default program was used to detect docking accuracy. Virtually, results showed that flavonoids have higher binding strength for apigenin and luteolin (which was -8.2 and -8.3) than Anastrozole (which was -7.6) with chain A of Aromatase. So, flavonoids can potentially be used as a natural medication to reduce breast cancer incidence. However, clinical trial studies are needed to investigate the role of apigenin and luteolin in the treatment of breast cancer.

Assessing Algerian Ilex aquifolium L.’s phenolic compounds, antioxidant and enzyme inhibitory properties to find a new natural remedy for Alzheimer’s, diabetes and skin diseases

This research explored the impact of methanolic extracts from the fruits and leaves of Ilex aquifolium L., a rare Algerian species, on several enzymes, focusing on tyrosinase, α-amylase, α-glucosidase, and cholinesterases, as well as their antioxidant potential in vitro assays, including phosphomolybdenum, DPPH, ABTS, CUPRAC, FRAP, and MCA. HPLC-DAD analysis identified chlorogenic acid, rosmarinic acid, hesperidin, and quercetin as predominant phenolic components. Both extracts exhibited notable antioxidant properties, up to 250.08 mg TE/g for fruits and 237.08 mg TE/g for leaf extracts. Enzyme inhibitory assays demonstrated significant inhibition against AChE and BChE with maximum activities of 2.34 mg GALAE/g in leaves and 4.32 mg GALAE/g in fruits. Additionally, considerable tyrosinase inhibition was observed in leaves at 39.69 mg KAE/g. These findings highlight I. aquifolium L. as a valuable source for investigating natural antioxidants and enzyme inhibitors, particularly for possible cosmetics and food additives applications.

Relationship between Natural Coagulation Inhibitor and Obstetrics History in Predicting Thromboembolic Events during Pregnancy

Background: There is a low level of information on natural coagulation inhibitors in this environment and whether the early detection of its deficiencies could serve as a risk assessment tool for thromboembolic events in pregnancy. This study aims to determine the relationship between natural coagulation inhibitors and obstetrics history in predicting thromboembolic events during pregnancy. Methods: The study was a comparative cross-sectional hospital-based study conducted among one hundred and fifty pregnant women and age-matched healthy non-pregnant control. Obstetrics history was obtained via questionnaire and other information was extracted from case notes. Blood specimens were obtained for laboratory assessment of natural coagulation inhibitors (Protein C, S, and antithrombin III) at various trimesters of pregnancy. Data were analyzed using SPSS version 23. Results: All NCIs decreased across the three trimesters of pregnancy but only the mean protein S and antithrombin III decreased with statistical significance (p = 0.001). Protein C, S, and antithrombin III did not show a statistically significant association when correlated with obstetrics histories. Conclusion: Although this study demonstrated a progressive decrease in the levels of NCIs across various trimesters of pregnancy, the use of NCIs as predictive tools for thromboembolic events in women with past bad obstetrics histories was not established but rather for risk assessment during pregnancy regardless of past obstetrics history.

Emerging Role of Natural Topoisomerase Inhibitors as Anticancer agents

Abstract: Topoisomerases I and II are the functionally two forms of DNA topoisomerase. In anticancer research, novel anticancer chemotherapeutical capable of blocking topoisomerase enzymes have been discovered. Most commonly, topoisomerase causes replication fork arrest and doublestrand breaks, and this is how a clinically successful topoisomerase-targeting anticancer medicines work. Unfortunately, this novel mechanism of action has been linked to the development of secondary malignancies as well as cardiotoxicity. The specific binding locations and mechanisms of topoisomerase poisons have been identified by studying the structures of topoisomerase-drug-DNA ternary complexes. Recent breakthroughs in science have revealed that isoform-specific human topoisomerase II poison could be created as safer anticancer drug molecules. It may also be able to develop catalytic inhibitors of topoisomerases by focusing on their inactive conformations. In addition to this, the discovery of new bacterial topoisomerase inhibitor molecules and regulatory proteins could lead to the discovery of new human topoisomerase inhibitors. As a result, biologists, organic chemists, and medicinal chemists worldwide have been identifying, designing, synthesizing, and testing a variety of novel topoisomerase-targeting bioactive compounds. This review focused on topoisomerase inhibitors, their mechanisms of action, and different types of topoisomerase inhibitors that have been developed during the last ten years.

Identification of Novel Target DCTPP1 for Colorectal Cancer Therapy with the Natural Small-Molecule Inhibitors Regulating Metabolic Reprogramming.

Colorectal cancer (CRC) is one of the most common malignant tumors. Identification of new effective drug targets for CRC and exploration of bioactive small-molecules are clinically urgent. The human dCTP pyrophosphatase 1 (DCTPP1) is a newly identified pyrophosphatase regulating the cellular nucleotide pool but remains unexplored as potential target for CRC treatment. Here, twelve unprecedented chemical architectures terpene-nonadride heterodimers (1-12) and their monomers (13-20) were isolated from endophyte Bipolaris victoriae S27. Compounds 1-12 represented the first example of terpene-nonadride heterodimers, in which nonadride monomers of 1 and 2 were also first example of 5/6 bicyclic nonadrides. A series of assays showed that 2 could repress proliferation and induce cell cycle arrest, apoptotic and autophagic CRC cell death in vitro and in vivo. Clinical cancer samples data revealed that DCTPP1 was a novel target associated with poor survival in CRC. DCTPP1 was also identified as a new target protein of 2. Mechanically, compound 2 bound to DCTPP1, inhibited its enzymatic activity, intervened with amino acid metabolic reprogramming, and exerted anti-CRC activity. Our study demonstrates that DCTPP1 was a novel potential biomarker and therapeutic target for CRC, and 2 was the first natural anti-CRC drug candidate targeting DCTPP1.