Browsing Pathways

Velpatasvir is a NS5A inhibitor used to treat chronic hepatitis C infections in patients without cirrhosis or with compensated cirrhosis, used as part of combination therapy to treat chronic Hepatitis C. Notably, velpatasvir has a significantly higher barrier to resistance than the first generation NS5A inhibitors, such as Ledipasvir and Daclatasvir, making it a highly potent and reliable alternative for treatment of chronic Hepatitis C. Hepatitis C virus lipoviroparticles enter target hepatocytes via receptor-mediated endocytosis. The lipoviroparticles attach to LDL-R and SR-B1, and then the virus binds to CD81 and subsequently claudin-1 and occludin, which mediate the late steps of viral entry. The virus is internalized by clathrin-dependent endocytosis. RNA is released from the mature Hepatitis C virion and translated at the rough endoplasmic reticulum into a single Genome polyprotein. The genome polyprotein is cleaved by host and viral proteases into 10 viral proteins. The nucleocapsid protein core and the two envelope proteins E1 and E2 form the N terminus of the polyprotein and are the structural components of HCV virions. The precursor also gives rise to the viroporin p7 and six non-structural (NS) proteins Velpatasvir is an inhibitor of the Hepatitis C Virus (HCV) Nonstructural protein 5A, which is required for viral RNA replication and assembly of HCV virions. The exact mechanism of this protein is unknown. Velpatasvir's mechanism of action is likely similar to other selective NS5A inhibitors which bind domain I of NS5A consisting of amino acids 33-202. NS5A inhibitors compete with RNA for binding at this site. It is also thought that NS5A inhibitors bind the target during its action in replication when the binding site is exposed. Viral RNA replication complexes localize to lipid raft-containing, detergent-resistant membranes created by the viral protein NS4B. For full viral replication and maturation, replication complexes need to be in close proximity to lipid droplets, which requires the protein nonstructural protein 5A. Without the lipid droplet due to inhibition of nonstructural protein 5A, full viral RNA replication is unable to occur. Envelope glycoproteins are acquired through budding into the endoplasmic reticulum lumen. The immature, non-infective virions are released via the cellular golgi apparatus.

Vatalanib is an anti-VEGFR molecule in the treatment of cancer. Cancer cells tend to overexpress VEGF, which stimulates angiogenesis, facilitating cancer growth and metastasis. The majority of VEGF’s effects are mediated through its binding to the VEGFR-2 receptor on endothelial cell surfaces. Upon binding, the receptor autophosphorylates and initiates a signalling cascade, starting with the activation of CSK. CSK phosphorylates Raf-1, which subsequently phosphorylates MAP kinase kinase, which phosphorylates MAP kinase. The activated MAP kinase enters the nucleus and stimulates the expression of angiogenic factors resulting in increased cell proliferation, migration, permeability, invasion, and survival. Binding of VEGF to VEGFR-2 also activates phospholipase C PIP2 into DAG and IP3. DAG may be involved in the activation of Raf-1 leading to angiogenesis, while IP3 activates PI3K and triggers calcium release from the endoplasmic reticulum. This ultimately leads to the activation of nitric oxide synthase and the production of nitric oxide, which stimulates vasodilation and increases vascular permeability. In cancer, VEGF has also been shown to bind to the VEGFR-1 receptor. However, its effects on angiogenesis are unclear at the moment. There are some evidence to show that VEGFR-1 may cross-talk with VEGFR-2 and initiate the signalling cascades described above. Vatalanib exerts its effect by binding to intracellular tyrosine kinase domain of VEGFR-2 and preventing receptor autophosphorylation and activation of downstream pathways, resulting in suppression of angiogenesis.

Vanoxerine is an investigational drug that is a selective dopamine transporter antagonist that has not been approved for therapeutic use but is indicated to help treat cocaine addiction. It was developed as a treatment for depression but was found to have a higher affinity for the dopamine reuptake transporter with a slower dissociation rate than cocaine, indicating its use in cocaine addiction. Vanoxerine does have a moderate potential to be abused by humans as it stimulates the nervous system through the reuptake of norepinephrine and dopamine, which prolongs their duration in the synapse so that they can bind more readily to the receptors. This drug can inhibit cocaine binding sites at the dopamine transporters. The mechanism is not fully understood, but may be similar to other dopamine reuptake inhibitors where Vanoxerine would cross the blood-brain barrier through diffusion. Dopamine is synthesized in the ventral tegmental area of the brain from tyrosine being synthesized into L-dopa by the enzyme Tyrosine 3-monooxygenase . L-Dopa is then synthesized into dopamine with the enzyme aromatic-L-amino-acid decarboxylase. Dopamine then travels to the prefrontal cortex, which is released into the synapse when the neuron is stimulated and fires. Vanoxerine binds to the sodium-dependent dopamine transporter, preventing dopamine from re-entering the presynaptic neuron. The dopamine then binds to Dopamine D4 receptors on the postsynaptic membrane. The dopamine D4 receptor activates the Gi protein cascade which inhibits adenylate cyclase. This prevents adenylate cyclase from catalyzing ATP into cAMP.