Browsing Pathways

Tenofovir is a nucleotide analog that has shown to be effective against HIV, herpes simplex virus-2, and hepatitis B virus. When HIV infects a cell, the virus first binds and fuses with the cell, releasing its nucleocapsid containing its RNA and reverse transcriptase into the cytosol of the cell. The reverse transcriptase converts the viral RNA into viral DNA in the cytosol. The viral DNA goes to the nucleus through the nuclear pore complex where it undergoes the process of transcription. The new viral RNA formed from transcription is transported back to the cytosol through the nuclear pore complex and translation occurs to produce viral proteins. These viral proteins are assembled and new HIV viruses bud from the cell. Tenofovir enters the cell via solute carrier family 22 member 8 and is converted into tenofovir monophosphate by adenylate kinase. Nucleoside diphosphate kinase then converts tenofovir monophosphate into tenofovir diphosphate. Tenofovir diphosphate is an analog of deoxyadenosine triphosphate (dATP). Tenofovir diphosphate inhibits the activity of HIV-1 reverse transcriptase by competing with its substrate, dATP and by incorporation into viral DNA. Tenofovir diphosphate lacks the 3'-OH group which is needed to form the 5′ to 3′ phosphodiester linkage essential for DNA chain elongation, therefore, once tenofovir diphosphate gets incorporated into DNA, this causes DNA chain termination, preventing the growth of viral DNA. Less viral proteins are therefore produced, and there is a reduction in new viruses being formed.

Tenofovir is a nucleotide analogue used in the treatment of HIV and chronic hepatitis B. It is taken up into the cell and is subsequently phosphorylated first by adenylate kinases and then by nucleoside diphosphate kinases into tenofovir diphosphate. Tenofovir diphosphate is an analogue of deoxyadenosine triphosphate (dATP) and competes with dATP for binding to the viral DNA polymerase and subsequent incorporation into the growing DNA strand. Once incorporated into the DNA, tenofovir causes chain termination, thus preventing viral replication.

Teniposide is a type of chemotherapy drug, derived from the epipodophyllotoxin form the American Mayapple plant. Teniposide is related to etoposide, another anti-cancer drug. It works in a similar way, inhibiting topoisomerase II. This causes single- and double-stranded DNA breaks. These breaks cause cell growth to stop and prevents cancer cells from entering mitosis. It is administered through an intravenous infusion. It is used to treat many cancers such as lymphoma, leukemia (acute lymphocytic), and neuroblastoma.

Tenecteplase is a plasminogen activator, a modified form of recombinant human tissue, also known as Metalyse and Tnkase, used in emergencies such as myocardial infarction and pulmonary emboli. It is administered intravenously and travels through the bloodstream to target blood clots by activating plasminogen. Tenecteplase acts on plasminogen by cleaving an arginine-valine bond and converting it to its active form of plasmin. Plasmin then acts on the blood clot fibrin mesh and degrades it into degradation products eliminating the blood clot. Due to its anticoagulant and antiplatelet activity herbs and supplements with similar activity should be avoided such as garlic, ginger, bilberry, danshen, piracetam and ginkgo biloba.

Tenecteplase is an enzyme that is part of the thrombolytics drug class, used to dissolve or break down blood clots. Tenecteplase activates plasminogen. Then zooming in even further to the endoplasmic reticulum within the liver, vitamin K1 2,3-epoxide uses vitamin K epoxide reductase complex subunit 1 to become reduced vitamin K (phylloquinone), and then back to vitamin K1 2,3-epoxide continually through vitamin K-dependent gamma-carboxylase. This enzyme also catalyzes precursors of prothrombin and coagulation factors VII, IX and X to prothrombin, and coagulation factors VII, IX and X. From there, these precursors and factors leave the liver cell and enter into the blood capillary bed. Once there, prothrombin is catalyzed into the protein complex prothrombinase complex which is made up of coagulation factor Xa/coagulation factor Va (platelet factor 3). These factors are joined by coagulation factor V. Through the two factors coagulation factor Xa and coagulation factor Va, thrombin is produced, which then uses fibrinogen alpha, beta, and gamma chains to create fibrin (loose). This is then turned into coagulation factor XIIIa, which is activated through coagulation factor XIII A and B chains. From here, fibrin (mesh) is produced which interacts with endothelial cells to cause coagulation. Plasmin is then created from fibrin (mesh), then joined by tissue-type plasminogen activator (tenecteplase) through plasminogen, and creates fibrin degradation products. These are enzymes that stay in your blood after your body has dissolved a blood clot. Coming back to the factors transported from the liver, coagulation factor X is catalyzed into a group of enzymes called the tenase complex: coagulation factor IX and coagulation factor VIIIa (platelet factor 3). This protein complex is also contributed to by coagulation factor VIII, which through prothrombin is catalyzed into coagulation factor VIIIa. From there, this protein complex is catalyzed into prothrombinase complex, the group of proteins mentioned above, contributing to the above process ending in fibrin degradation products. Another enzyme transported from the liver is coagulation factor IX which becomes coagulation factor IXa, part of the tense complex, through coagulation factor XIa. Coagulation factor XIa is produced through coagulation factor XIIa which converts coagulation XI to become coagulation factor XIa. Coagulation factor XIIa is introduced through chain of activation starting in the endothelial cell with collagen alpha-1 (I) chain, which paired with coagulation factor XII activates coagulation factor XIIa. It is also activated through plasma prekallikrein and coagulation factor XIIa which activate plasma kallikrein, which then pairs with coagulation factor XII simultaneously with the previous collagen chain pairing to activate coagulation XIIa. Lastly, the previously transported coagulation factor VII and tissue factor coming from a vascular injury work together to activate tissue factor: coagulation factor VIIa. This enzyme helps coagulation factor X catalyze into coagulation factor Xa, to contribute to the prothrombinase complex and complete the pathway.

Temozolomide (TMZ) is an antineoplastic from the alkylating agent drug class. This molecule is an imidazotetrazine prodrug that is stable at acidic pH but undergoes spontaneous nonenzymatic hydrolysis at neutral or slightly basic pH; allowing its administration to be oral and intravenous too. Temozolomide is indicated in the treatment of newly diagnosed glioblastoma and refractory anaplastic astrocytoma. This molecule is a very small lipophilic, it can then easily get through the blood-brain barrier. The mechanism of action of this drug needs many reactions beforehand: TMZ undergoes spontaneous nonenzymatic breakdown at physiological pH to form 5-(3-methyltriazen-1-yl) imidazole-4-carboxamide (MTIC), which then reacts with water to produce 5-aminoimidazole-4-carboxamide (AIC) and a highly reactive methyl diazonium cation. TMZ is a bit specific to tumor cells because glioblastoma typically possesses a more alkaline pH than healthy tissue, favoring its activation in tumor cells. The methyl diazonium cation formed methylates DNA at the N7 and O6 position of guanine, and the N3 position of adenine. The cellular repair system will eventually lead to DNA strand breaks that will end in the apoptosis of the cell.