Pathways

Nirmatrelvir is an oral protease inhibitor with emergency use authorization for the treatment of mild-to-moderate COVID-19. In December 2021 Paxlovid, a co-package of nirmatrelvir and ritonavir, was granted emergency use by the FDA. Paxlovid was approved for use in Canada in January 2022 for the treatment of adult patients with mild-moderate COVID-19. Later, it was granted conditional marketing authorization by the European Commission on January 27, 2022. Severe acute respiratory syndrome conronavirus 2 (SARS-CoV-2) is the causative agent of COVID-19, and is a respiratory disease that is capable of progressing to viral pneumonia and acute respiratory distress syndrome (ARDS). COVID-19 can be fatal. Like other RNA viruses, SARS-CoV-2 depends on RNA-dependent RNA polymerase (RdRp) for genomic replication. SARS-CoV-2 lipoviroparticles enter target hepatocytes via receptor-mediated endocytosis. Viral RNA is released from the mature SARS-CoV-2 virion and translated at the endoplasmic reticulum. SARS-CoV-2 RNA is translated into Replicase polypotein 1ab by host ribosomes. Replicase Protein 1ab is regularly cleaved by SARS-CoV-2 3C-like proteinase nsp5 and Papain-like protease nsp3 into various proteins required for RNA replication, mature virus synthesis, and the enzymes required for the cleavage of the polyprotein. These proteins include host translation inhibitor nsp1, non-structural protein 2, papain-like protease nsp3, non-structural protein 4, 3C-like proteinase nsp5, non-structural protein 6, non-structural protein 7, non-structural protein 8, RNA-capping enzyme subunit nsp9, non-structural protein 10, RNA-directed RNA polymerase nsp12, helicase nsp13, guanine-N7 methyltransferase nsp14, uridylate-specific endoribonuclease nsp15, and 2'-O-methyltransferase nsp16. SARS-CoV-2 RNA that was released from the virus is normally replicated by RNA polymerase which is comprised of nsp7, nsp8, and nsp12. Nimatrelvir inhibits a cysteine residue in 3C-like protease (3-CL) of SARS-CoV-2, which is the main protease that cleaves replicase polyprotein 1ab. The cysteine is responsible for the activity of the 3CL. This prevents the polyprotein from being cleaved into the various nonstructural proteins required for viral RNA replication, including proteases. SARS-CoV-2 RNA that was released is prevented from replicating due to the inhibition of polyprotein cleavage. Due to the inhibition of RNA replication, mature, infective viruses are unable to be assembled and released.

Nisoldipine is a 1,4-dihydropyridine calcium channel blocker. It acts primarily on vascular smooth muscle cells by stabilizing voltage-gated L-type calcium channels in their inactive conformation. By inhibiting the influx of calcium in smooth muscle cells, nisoldipine prevents calcium-dependent smooth muscle contraction and subsequent vasoconstriction. Nisoldipine may be used in alone or in combination with other agents in the management of hypertension. (DrugBank) By deforming the channel, inhibiting ion-control gating mechanisms, and/or interfering with the release of calcium from the sarcoplasmic reticulum, Nisoldipine inhibits the influx of extracellular calcium across the myocardial and vascular smooth muscle cell membranes The decrease in intracellular calcium inhibits the contractile processes of the myocardial smooth muscle cells, causing dilation of the coronary and systemic arteries, increased oxygen delivery to the myocardial tissue, decreased total peripheral resistance, decreased systemic blood pressure, and decreased afterload. (DrugBank)

Nisoldipine (also known as Sular or Nisocor) is a dihydropyridine calcium channel blocker that may be used for treatment of hypertension, chronic stable angina and Prinzmetal's variant angina. Nisoldipine binds the major channel in muscle cells: L-type calcium channels. Binding of Nisoldipine on L-type calcium channels can change channels' confirmation to its inactive form, so that the channel couldn't faciltate the influx of calcium ions, which leads to decreased arterial smooth muscle contractility and subsequent vasoconstriction. Activated mysoin light chain kinase (MLCK) is required for muscle contraction since it can catalyze the phosphorylation of the regulatory light chain subunit of myosin. Without calcium ions in muscle cell, calmodulin couldn't form the calcium-bound calmodulin, which is required for binding and activating MLCK. Lack of initial influx of calcium can also reduce the level of contractile activity of muscle cells and results in vasodilation, which ultimately lead to overall decresing in blood pressure.

Nisoldipine is a calcium channel blocker used as monotherapy or combined with other drugs for the treatment of hypertension. It can be found under the brand name Sular. Nisoldipine is a 1,4-dihydropyridine calcium channel blocker. It acts primarily on vascular smooth muscle cells by stabilizing voltage-gated L-type calcium channels in their inactive conformation. By inhibiting the influx of calcium in smooth muscle cells, nisoldipine prevents calcium-dependent smooth muscle contraction and subsequent vasoconstriction. Nisoldipine may be used in alone or in combination with other agents in the management of hypertension. By deforming the channel, inhibiting ion-control gating mechanisms, and/or interfering with the release of calcium from the sarcoplasmic reticulum, Nisoldipine inhibits the influx of extracellular calcium across the myocardial and vascular smooth muscle cell membranes. It targets the alpha-1C, alpha-2/delta-1, beta-2, alpha-1D, and alpha-1S subunits of the channel. The decrease in intracellular calcium inhibits the contractile processes of the myocardial smooth muscle cells, causing dilation of the coronary and systemic arteries, increased oxygen delivery to the myocardial tissue, decreased total peripheral resistance, decreased systemic blood pressure, and decreased afterload. Nisoldipine is administered as an oral tablet. Some side effects of using nisoldipine may include headache, upset stomach, dizziness, and flushing.

NADH dehydrogenase and nitrate reductase can form the anaerobic respiratory chain that can be used for transferring electrons from NADH to nitrate with proton-motive force across cytoplasmic membrane. In E. coli K-12, NDH-I and NDH-II is the two energy conserving NADH dehydrogenases that do not contribute to proton gradient; but both of the enzymes are involved in anaerobic nitrate respiration. NDH-I might be acted as proton pump for translocating 4H+ per NADH oxidised (2e-). In E. coli K-12, there are also two energy conserving (H+/e- = 1) nitrate reductases (nitrate reductase A (NRA) and nitrate reductase Z (NRZ)). Nitrate reductase A can express under the condition of high levels of nitrate in environment; while the expression of nitrate reductase Z doesn't depend on nitrate levels or anaerobiosis. Nitrate and hydrogen atom will be catalyzed to form nitrite and water during nitrate reduction.