Pathways

Paritaprevir is a direct acting antiviral agent used in combination with other antiviral agents for the treatment of Hepatitis C Virus (HCV) infections. 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. Paritaprevir accumulates in the liver after uptake into hepatocytes via solute carrier organic anion transporter family member 1B1. Paritaprevir inhibits NS3/4A protease, which is an enzyme that cleaves the heptatitis C virus polyprotein downstream of the NS3 proteolytic site, which generates nonstructural proteins NS3, NS4A, NS4B, NS5A, and NS5B. These proteins are required in viral RNA replication, therefore because of the inhibition of their formation, RNA replication cannot occur. Because RNA replication does not occur, the mature virion is unable to form. At higher concentration above their antiviral half-maximal effective concentration (EC50), Paritaprevir and other NS3/4A inhibitors also restore interferon (IFN)-signaling pathways that are thought to be disrupted by NS3/4A protease and recover innate immune processes. NS3/4A protease cleaves two essential adaptor proteins that initiate signaling leading to activation of IFN regulatory factor 3 and IFN-α/β synthesis, which are mitochondrial antiviral-signaling proteins.

Telaprevir is an NS3/4A viral protease inhibitor used in combination with other antivirals for the curative treatment of chronic Hepatitis C Virus infections. 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. Paritaprevir accumulates in the liver after uptake into hepatocytes via solute carrier organic anion transporter family member 1B1. Paritaprevir inhibits NS3/4A protease, which is an enzyme that cleaves the heptatitis C virus polyprotein downstream of the NS3 proteolytic site, which generates nonstructural proteins NS3, NS4A, NS4B, NS5A, and NS5B. These proteins are required in viral RNA replication, therefore because of the inhibition of their formation, RNA replication cannot occur. Because RNA replication does not occur, the mature virion is unable to form. At higher concentration above their antiviral half-maximal effective concentration (EC50), Paritaprevir and other NS3/4A inhibitors also restore interferon (IFN)-signaling pathways that are thought to be disrupted by NS3/4A protease and recover innate immune processes. NS3/4A protease cleaves two essential adaptor proteins that initiate signaling leading to activation of IFN regulatory factor 3 and IFN-α/β synthesis, which are mitochondrial antiviral-signaling proteins.

Boceprevir is a hepatitis C virus NS3/4A protease inhibitor used in combination with other medications to treat chronic hepatitis C genotype 1 infection. 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. Boceprevir accumulates in the liver after uptake into hepatocytes via solute carrier organic anion transporter family member 1B1. Boceprevir inhibits NS3/4A protease, which is an enzyme that cleaves the heptatitis C virus polyprotein downstream of the NS3 proteolytic site, which generates nonstructural proteins NS3, NS4A, NS4B, NS5A, and NS5B. These proteins are required in viral RNA replication, therefore because of the inhibition of their formation, RNA replication cannot occur. Because RNA replication does not occur, the mature virion is unable to form.

Grazoprevir is an antiviral and non-structural 3/4A protease inhibitor used to treat hepatitis C infections in combination with other drugs. 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. Grazoprevir accumulates in the liver after uptake into hepatocytes via solute carrier organic anion transporter family member 1B1. Grazoprevir inhibits NS3/4A protease, which is an enzyme that cleaves the heptatitis C virus polyprotein downstream of the NS3 proteolytic site, which generates nonstructural proteins NS3, NS4A, NS4B, NS5A, and NS5B. These proteins are required in viral RNA replication, therefore because of the inhibition of their formation, RNA replication cannot occur. Because RNA replication does not occur, the mature virion is unable to form.

Voxilaprevir is a nonstructural protein 3 and 4a protease inhibitor used to treat Hepatitis C infections. 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. Voxilaprevir accumulates in the liver after uptake into hepatocytes via solute carrier organic anion transporter family member 1B1. Voxilaprevir inhibits NS3/4A protease, which is an enzyme that cleaves the heptatitis C virus polyprotein downstream of the NS3 proteolytic site, which generates nonstructural proteins NS3, NS4A, NS4B, NS5A, and NS5B. These proteins are required in viral RNA replication, therefore because of the inhibition of their formation, RNA replication cannot occur. Because RNA replication does not occur, the mature virion is unable to form.

Fostemsavir is the phosphonooxymethyl prodrug of temsavir, which is a HIV-1 attachment inhibitor that binds to the gp120 subunit within the HIV-1 gp160 envelope glycoprotein. Fostemavir is the first attachment inhibitor to receive FDA approval, granted in July 2020, for use in combination with other antretrovirals. The gp120 subunit within the gp160 envelpe glycoprotein of HIV-1 are responsible for facilitating attachment of the virus to the host cell CD4 receptors. Fostemsavir is metabolized in the microvilli of the small intestine into temsavir by the enzyme Intestinal-type alkaline phosphatase. It is transported into the blood where temsavir inhibits the envelope glycoprotein of HIV-1 by binding directly to the gp120 subunit, which inhibits the viral interaction with host CD4 receptors, thereby preventing the initial attachment of the virus. It has also been shown to inhibit other gp120-dependent post-attachment steps required for viral entry. The inability for the virus to attach and release viral components into the host cell greatly reduces the replication of the virus.

Enfuvirtide is an HIV-1 gp41 fusion inhibitor used in patients experiencing HIV-1 replication who are already being treated with other anti-retrovirals. Enfuvirtide is a biomimetic peptide that was rationally designed to mimic components of the HIV-1 fusion machinery and displace them, preventing normal fusion. Enfuvirtide inhibits the envelope glycoprotein by binding to the first heptad-repeat in the gp41 subunut. This disrupts the final stage of fusion with the host cell, thereby preventing the initial attachment of the virus. This significantly decreases viral replication which limits the spread of further infection.

Remdesivir is a nucleoside analog used to treat RNA virus infections, including COVID-19, a disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Remdesivir was granted FDA emergency use Authorization on May 1, 2020, for use in adults and children with suspected or confirmed COVID-19 infection requiring hospitalization. It was fully approved by the FDA on October 22, 2020 for the treatment of COVID-19. The mechanism of the drug were found to be identical between SARS-CoV, SARS-CoV-2, and MERS-CoV. 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. Due to the much higher selectivity of mammalian DNA and RNA polymerases for ATP over remdesivir triphosphate, remdesivir is not a significant inhibitor of these mammalian enzymes. Remdesivir does, however, carry the risks for hypersensitivity reactions, including anaphylaxis, elevated transaminase levels and potential decreased efficacy when combined with hydroxychloroquine or chloroquine. 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 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. Remdesivir is a phosphoramidite produg of a 1'-cyano-substituted adenosine nucleoside analogue that competes with ATP for incorporation into newly synthesized viral RNA by the RdRp complex. Remdesivir is cleaved to a monophosphate form through the actions of either carboxylesterase 1 or cathepsin A enzymes. Remdesivir nucleoside monophosphate is then phosphylated by undescribed kinases to remdesivir nucleoside triphosphate. Remdesivir Nucleoside Triphosphate inhibits RNA polymerase, by competing with ATP for incorporation into newly synthesized viral RNA. This prevents RNA replication from occurring. Because RNA replication does not occur, mature, infective viruses are unable to be assembled and released.

Cefmenoxime is a novel broad-spectrum and third-generation cephalosporin antibiotic that is typically used in the treatment of female gynecologic and obstetric infections. It is reported to exhibit high activity against a wide variety of gram-positive and gram-negative bacteria. Used to treat female gynecologic and obstetric infections caused by susceptible aerobic (including the gonococcus) and anaerobic bacteria. The bactericidal activity of cefmenoxime results from the inhibition of cell wall synthesis via affinity for penicillin-binding proteins (PBPs). Cefmenoxime is stable in the presence of a variety of b-lactamases, including penicillinases and some cephalosporinases.

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.