Enzyme Inhibitors

5-Fluorouracil (5-FU) is a uracil analog that has a fluorine atom on the fifth carbon position. It acts as a strong anti-cancer agent where its metabolization disrupts both RNA and DNA synthesis. 5-FU metabolites, Fluorodeoxyuridine triphosphate (FdUTP) and fluorouridine triphosphate (FUTP), imitate uracil and are incorporated into RNA strands which effectively inhibits further synthesis.

Inhibition of DNA synthesis by 5-FU occurs through thymidylate synthase inhibition. A metabolite produced by 5-FU metabolism, fluorodeoxyuridine triphosphate (FdUTP), bind to the nucleotide binding site of thymidylate synthase. Halting this enzyme’s activity significantly diminishes deoxythymidine monophosphate (dTMP) production which consequently depletes dTMP within an organism.

8-Hydroxyquinoline is an organic compound that is used as a RNA inhibitor, anti-cancer agent and bidentate chelating agent. In vitro studies against Escherichia coli had shown 8-hydroxyquinoline inhibiting RNA polymerase activity. The enzyme’s activity was inhibited by chelating manganese, magnesium or zinc cofactors. Activity of 8-hydroxyquinoline toward RNA polymerase is broad and inhibits the synthesis of vertebrate RNA as well as proteins.

8-Hydroxyquinoline has also been used as an immobile chelating agent to remove transition metals, alkali and alkaline cations from solutions or within organisms. Its capability to bind the positively charged metals has been shown in vivo to inhibit proteasome activity in tumor cells by transporting copper ions into malignant cells. Halting proteasome activity was observed in vitro and in vivo with decreased cancer growth due to apoptosis.

Acalabrutinib (ACP-196) is an irreversible inhibitor of Bruton’s tyrosine kinase (BTK), which is responsible for the maturation of B-cells. Its high selectivity to bind the residue Cys481 in the active site of BTK is a sought after feature for oncology research. Studies on mice and human cells demonstrate the high affinity of ACP-196 and its low affinity toward similar proteins in T-cell maturation.

Acycloguanosine is a guanosine analogue that is synthetically formed. It is markedly effective against the herpesvirus family, especially HSV (herpes simplex viruses) types one and two. Lab results have shown susceptibility to acycloguanosine which varies with the analogue’s concentration, respective to each virus.

Acycloguanosine functions as a HSV DNA polymerase inhibitor by integrating into the viral DNA, terminating polymerization. Integration occurs after being catalyzed by viral thymidine kinase into acyclovir triphosphate (Acyclo-GTP). Acycloguanosine is ineffective against non-viral genetic material, due to the lack of an appropriate thymidine kinase.

Ampicillin/sulbactam (2:1) is a broad-spectrum combination of a β-lactam antibiotic with a β-lactamase inhibitor. It is used for in vitro susceptibility tests in microbiology, pharmacokinetics and pharmacodynamics studies.

Ampicillin binds to the active site of penicillin binding proteins (PBP), preventing peptidoglycan cross-link formation of the bacterial cell wall. Inhibition of PBPs weakens the bacterial cell wall and leads to cell lysis. Sulbactam irreversibly inhibits β-lactamase enzymes generated by bacteria, preserving ampicillin activity and enhancing potency.

Aprotinin is a monomeric globular polypeptide derived from bovine lung tissue. It consists of a chain of 58 amino acids that fold into a stable, compact tertiary structure of the 'small SS-rich" type, containing 3 disulfides, a twisted β-hairpin and a C-terminal α-helix.

Aprotinin inhibits several serine proteases, specifically trypsin, chymotrypsin, plasmin and kallikrein. Its action on kallikrein leads to the inhibition of the formation of factor XIIa. Binding is reversible with most aprotinin-protease complexes dissociating at pH >10 or < 3. Aprotinin is freely soluble in water (>10 mg/ml) as well as low ionic strength aqueous buffers.

Artesunate is a synthetic compound that is highly employed for its anti-malarial capabilities and is currently studied for its applications in oncology research and surgical procedures. In anti-malarial studies, it has been shown to disrupt EXP1 activity, which is a glutathione transferase responsible for cell detoxification in Plasmodium falciparum. Artesunate activity has been shown to be enhanced when co-administered with amodiaquine HCl.

In oncology research, Artesunate is used to arrest cancer growth in the G2/M phase and upregulate proteins p21 and Beclin1. These proteins are mainly related to apoptosis with p21 being a regulator of the process and Beclin1 playing a role in cell death by autophagy. Artesunate has also been shown to form an endoperoxide bridge which generates carbon radicals that dismantle the cell. However, the observed radical formation is dose and time dependent.

Artesunate has been shown to provide organ damage reduction in rats exposed to hemorrhagic shock. Administration of ART occurred after resuscitation and did not function as a preventative. Artesunate operates by decreasing cell apoptosis through protein kinase B (PKB) stimulation and glycogen synthase kinase inhibition. Cell survival is also enhanced by nuclear factor kappa B (NfkB) suppression, diminishing proinflammatory cytokine synthesis.

Baicalin is a flavone glycoside formed from the glucuronidation of baicalein. It has an array of properties which include promoting cell survival and bolstering the immune system. One of the effects that baicalin produced with in vitro studies of pathogens and in vivo studies on rats and mice was an elevation in cell survival, which implied the prevention of cell death due to induced apoptosis or the accumulation of oxidative species. Apoptotic repression occurred in rats due to a decreased expression of proteins within the CHOP (C/EBP homologous protein) pathway. Stimulating the synthesis of endothelial nitrogen oxides (eNOS) and other nitrogen oxides quell oxidative stress with the termination of free radicals.

Additionally, protective effects of baicalin have specifically diminished injury in the hippocampal area. Baicalin has been shown to stimulate the expression of Bcl-2 (B-cell lymphoma-2) which regulates apoptosis. It has also been shown to decrease miR-497 expression and cleave caspase-3 protein synthesis. These play roles in regulating gene expression and nervous system cell apoptosis respectively.

Enhancing the immune response with baicalin has proven effective in two ways. One observed effect was the induction of IFN-γ cytokine production in mice, a cytokine which activates macrophages and MHC II (major histocompatibility complex II) expression. Lysozyme bacteriostatic duration was shown to increase when exposed to increasing concentrations of baicalin.

Bakuchiol is a terpenophenolic compound extracted from the plant Psoralea corylifolia. Bakuchiol has been used as an oral antibiotic, anti-tumor agent and for the protection of liver and bone tissue. It has also been used as an insulin enhancer to counter hyperglycemia and hyperlipidemia for in vivo research on mice and rats. Within these studies, bakuchiol inhibited phospho-tyrosine protein phosphatase type 1B (PTP1B), DNA polymerase and topoisomerase II. Inactivity of these three enzymes greatly reduced PTPB1 activity, which has been found to suppress insulin signaling.

Antibiotic and anti-tumor uses of bakuchiol have been shown to be correlated to suppression of DNA synthesis. As a bactericidal agent, bakuchiol has been proven to be robust in vitro and is functional at many pH values as well as in the presence of organic acids. Bakuchiol terminates bacteria and malignant cells by generating intracellular reactive oxygen species (ROS), dismantling bacterial cells and compromising tumor cell mitochondria. Conversely, bakuchiol has also been shown to preserve liver function by inhibiting ROS that cause lipid peroxidation and the use of glutathione, an antioxidant.

The bone preserving effects of bakuchiol are related to its high binding affinity for estrogen receptor alpha (ERα). It has been shown that bakuchiol stimulates ERα to promote bone protective pathways.The pathways controlled by ERα increase alkaline phosphatase, calcium concentration, estradiol concentration and a decrease in inorganic phosphate level.

Bithionol is an anti-parasitic compound used for oncology research and molecular biology research. It induces apoptosis in cancerous cells occurs through activating proteolytic caspases. These caspases inactivate PARP-1(Poly [ADP-ribose] polymerase 1) which triggers an intrinsic pathway for apoptosis. Intrinsic apoptotic pathways result in compromising mitochondria and in this case by decreasing transmembrane potential. Reactive oxygen species then accumulate and rupture the mitochondria, releasing cytochrome c an apoptotic inducer.

Bithionol has been used to better understand enzyme allosteric regulation and the mechanism of soluble adenylyl cyclase inhibition, a bicarbonate sensor. Bithionol has been shown to occupy the bicarbonate binding site on soluble adenylyl cyclase. It has also been utilized in research to elucidate the role of mitochondrial potassium channels in preventing ischemia reperfusion injuries in mice.

Bleomycin A5 hydrochloride is a compound part of the glycopeptide antibiotic family. It is currently used in oncology research for its strong stimulatory and inhibitory effects. Bleomycin A5 greatly reduces telomerase activity, hindering the proliferation of malignant cells. It has also been shown to induce in vivo fibrosis and inflammation by generating peroxynitrites, a strong oxidizing agent.

Bleomycin A5 stimulates downstream apoptosis by increasing cysteine-aspartic acid protease-3 (caspase-3) activity, tumor protein 53 (p53) production and transforming growth factor beta 1 (TGF-beta 1) formation. These proteins induce apoptosis directly or indirectly by halting cell growth.

Bulbocapnine hydrochloride is the water-soluble form of the bulbocapnine alkaloid group, substances which act as acetylcholinesterase and tyrosine hydroxylase inhibitors. Activity from these chemicals causes dopamine biosynthesis to stall. Bulbocapnine hydrochloride is therefore a dopamine receptor antagonist but has also been used as a tyrosine 3-monooxygenase inhibitor (EC 1.14.16.2) and diamine oxidase inhibitor (EC 1.4.3.22). Because bulbocapnine is a plant metabolite, the substance has been responsible for lethal poisoning in livestock.

Camptothecin is an alkaloid compound used as an anti-cancer agent. It is a topoisomerase I inhibitor in DNA synthesis. Camptothecin has been shown to bind and stabilize a topoisomerase I-DNA complex in vitro, preventing the enzyme from reannealing DNA strands. This inhibition specifically effects the S-phase of cell development and ultimately results in apoptosis due to damaged DNA.

Camptothecin is produced by endosymbiotic fungi, from the division Ascomycota (Phycomycete), that are present in the tree Camptotheca acuminata which is native to southern China. Camptothecin (Mappia foetida), (GoldBio Catalog # C-565) has also been isolated from fungi on Mappia foetida (Nothapodytes foetida), a plant common to India.

Camptothecin is an alkaloid compound used as an anti-cancer agent. It is a topoisomerase I inhibitor in DNA synthesis. Camptothecin has been shown to bind and stabilize a topoisomerase I-DNA complex in vitro, preventing the enzyme from reannealing DNA strands. This inhibition specifically effects the S-phase of cell development and ultimately results in apoptosis due to damaged DNA.

Camptothecin is found in Mappia foetida (Nothapodytes foetida), a plant native to eastern India. The compound itself is produced by an endosymbiotic Ascomycota (Phycomycete) fungi. Camptothecin (Camptotheca acuminata), (GoldBio Catalog # C-705) has also been produced by endosymbiotic fungi present in Camptotheca acuminata, which is a tree predominantly found in southern China.

Camptothecin sodium is sodium salt of an alkaloid compound camptothecin, which is used for cancer research. Camptothecin is produced from endosymbiotic Ascomycota (Phycomycete) fungi present in the tree Camptotheca acuminata or the plant Mappia foetida.

Camptothecin sodium is a topoisomerase I inhibitor in DNA synthesis. It has been shown to bind and stabilize a topoisomerase I-DNA complex in vitro, preventing the enzyme from reannealing DNA strands. This inhibition specifically effects the S-phase of cell development and ultimately results in apoptosis due to damaged DNA.

Cefditoren pivoxil is a β-lactam, cephalosporin antibiotic that has shown to be effective against an array of gram positive and negative bacteria. In vitro studies have exhibited cefditoren pixovil to have strong activity towards methicillin and penicillin-susceptible pathogens as well as penicillin-resistant Streptococcus pneumoniae.

Cephalosporins are a type of β-lactam antibiotic consisting of a four-membered β-lactam ring bound to a six-membered dihydrothiazine ring. This two-ring system causes distortion of the β-lactam amide bond, resulting in decreased resonance stabilization and increased reactivity. β-lactams inhibit the formation of peptidoglycan cross-links within bacterial cell walls by targeting penicillin-binding proteins or PBPs. Consequently, the bacterial cell wall becomes weak and cytolysis occurs. Cephalosporin compounds are less susceptible to β-lactamases than the penicillin β-lactam antibiotics.

Antibiotics are often used in clinical in vitro tests known as antimicrobial susceptibility tests or ASTs to determine their efficacy against certain bacterial species. They are tested against gram-negative and gram-positive bacteria using panels, discs, and MIC strips by medical microbiologists. ASTs decrease the risk of using an antibiotic against bacteria exhibiting resistance to it, and the results are used in clinical settings to determine which antibiotic(s) to prescribe for various infections.

Chicoric acid is a hydroxycinnamic acid that occurs in a variety of plants such as Cichorium intybus and Echinacea purpurea. It has been used as an anti-viral, anti-inflammatory, antioxidant and an insulin enhancer.

Chicoric acid has specifically been used as an inhibitor of integrase enzymes in human immunodeficiency virus type one (HIV1). Inhibition of this enzyme prevents viral genetic material from being incorporated into host DNA. It specifically shows activity towards HIV1 and not HIV2.

Chicoric acid presence for in vivo and in vitro studies have shown a stimulation in AMP-activated protein kinase (AMPK) expression. The upregulation in AMPK expression results in the observed antioxidant, anti-inflammatory and insulin enhancing effects. Anti-oxidizing protein synthesis has been increased through AMPK stimulation. AMPK has also been shown to diminish inflammatory responses by increasing interleukin 10 synthesis (IL10), an anti-inflammatory cytokine. Chicoric acid stimulation of AMPK inhibits glucose-6-phosphate formation, promoting glucose utilization. The release of insulin by pancreatic β-islet cells has been correlated with direct stimulation by chicoric acid.