Steph: Antiviral Drugs Flashcards
(20 cards)
Nucleoside Reverse Transcriptase Inhibitors (NRTI)
Abacavir; Lamivudine; Tenofovir disoproxil; Zidovudine (AZT); Emtricitabine
HIV-1 Protease Inhibitors
Atazanavir; Ritonavir
Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Efavirenz; Nevirapine
Fusion Inhibitors
Enfuvirtide; Maraviroc
DNA Strand Transfer Inhibitor
Raltegravir
Current uses for antiviral drugs
The HIV, the Herp, the Hep (A and B), and influenza
Classic Antiviral Med Targets
Viral DNA polymerase; reverse transcriptase; attachment and entry; uncoating; assembly and maturation; egress and release
Adamantane and Rimantadine (A and B)
Zanamivir and Oseltamivir (C and D)
Enemy: Influenza A
MOA/Target: (A & B): Block the action of the viral M2 protein during uncoating of the virus; (C & D): target neuraminidase, which is required for release of progeny virus from cell surface
What does that mean? The influenza A virus protein hemagglutinin binds host and enters via receptor-mediated endocytosis. This early endosome has a H+ ATPase that acidifies the endosome by pumping protons from cytoplasm into endosome, leading to fusion of viral membrane with endosomal membrane. Next, those protons must enter the virus through M2, a pH-gated proton channel in the viral envelope that opens in response to acidification. These actions cause uncoating of the virus so that it can release its ribonucleoprotein and begin replication.
Enfuvirtide (A) and Maraviroc (B)
Enemy: HIV
MOA/Target: (A): Mimics HR2 so that it can bind HR1 and prevent the real HR2:HR1 interaction, thereby trapping virus:host interaction at attachment and preventing membrane fusion and viral entry; (B): antagonist of CCR5 chemokine receptor; protects against strains that use CCR5 for attachment and entry (CCR5 not used by all HIV, so drug specific to those that do)
What does that mean? HIV looks like a group of three balloons. The balloons each have a gp 120 molecule, and the strings to which they’re tied have a gp 41 molecule. Gp 120 binds CD4 and other chemokines such as CCR5, causing a conformational change in gp 41 that exposes the fusion peptide, HR1/HR2. The fusion peptide inserts into the host membrane. Gp 41 undergoes further conformational changes that lead to refolding of HR regions, which then leads to fusion of the viral and host cell membranes. A complete fusion pore is created, allowing the virus to enter the cell.
Nucleoside reverse transcriptase inhibitors (NRTIs) require __________
metabolic activation, usually to a triphosphate form, before they can be incorporated into the growing DNA chain. Their incorporation typically leads to termination of chain elongation.
(Val)Acyclovir; (Val)Ganciclovir
Enemy: The herp 1 and 2; varicella zoster virus; cytomegalovirus (GAN)
General Info: The (val) form => these are orally absorbed pro-drugs that rapidly liberate the active agent upon entry into circulation, avoiding poor bioavailability.
MOA/Target: pppACV (the drug) acts as a competitive inhibitor of dGTP binding. It, instead of dGTP, becomes incorporated into the growing DNA chain and proceeds to terminate the growing DNA chain. It also traps the viral DNA polymerase on the ACV-terminated DNA chain when the next dNTP tries to bind.
Abacavir; Lamivudine (3-TC); Tenofovir disoproxil; Emtricitabine; Zidovudine (AZT) =» Rent Shout-Out: “AZT break” Boom. They both have the same virus AND love each other.
Enemy: HIV and sometimes HBV
MOA/Target: Provide competitive inhibition of viral reverse transcriptase by competing with endogenous nucleosides for incorporation into viral DNA. Once incorporated, they cause chain termination and inhibit viral replication.
Additional Info:
The HIV comes with reverse transcriptase included. Reverse transcriptase is a DNA polymerase that can copy both RNA and DNA.
These NRTIs are converted to triphosphate nucleotides by host cell kinases.
Binding of the drugs INDIRECTLY inhibits polymerase due to lack of specificity; therefore, they can also inhibit host cell DNA polymerase, leading to mitochondrial dysfunction; this accounts for the TOXICITIES associated with these drugs.
Mutations called TAMs (thymidine analog mutations) are associated with these drugs.
Efavirenz and Nevirapine
Enemy: HIV-1 ONLY (not HIV-2)
MOA/Target: Hydrophobic pocket in the p66 subunit of the HIV-1 reverse transcriptase; Impedes enzyme activity.
What does that mean? When the drugs bind that specific pocket (which, by the way, is distinct from the NRTI target), they alter the 3D structure of the enzyme and greatly impede its activity. The binding site is virus-strain-specific and works only against HIV-1.
Additional Info:
NRTIs and NNRTIs are non-competitive inhibitors due to different binding sites.
Do NOT require intracellular phosphorylation to attain activity.
Raltegravir
Enemy: HIV-1 and -2
MOA/Target: Blocks the catalytic activity of the HIV-1 & -2 encoded integrase, thus preventing integration of virus DNA into the host chromosome.
Additional Info:
This drug is still effective against the HIV, unlike many of its other antiretroviral buddies; however, due to its unique target, the virus can still become resistant to it via mutations in the integrase gene.
Atazanavir and Ritonavir
Enemy: HIV-1
MOA/Target: Aspartyl protease enzyme; prevents metamorphosis of HIV virus particles into their mature infectious form.
What does that mean? This drug is an inhibitor of the virus aspartyl protease enzyme that is responsible for proteolytic cleavage of the HIV gag and pol precursor polypeptides that include essential structural and enzymatic components of the virus. This prevents the metamorphosis of the HIV virus particles into their mature infectious form.
Additional Info:
Ritonavir can inhibit CYP3A4. It is typically used in low doses in combination with other agents to prolong their presence.
Boceprevir and Telaprevir
Enemy: Hepatitis C
Target/MOA: Cleavage of precursor peptides in Hepatitis C.
What does that mean? Following infection in the host, the single-stranded Hep-C RNA is translated into a single polyprotein that is cleaved into 10 proteins by signal peptidase, NS2/3 protease, and NS3/4A serine protease. The drug prevents formation of several of those critical, non-structural proteins.
Additional Info:
Hep C rapidly proliferates, so mutations can arise so quickly that the drug soon become obsolete for that person.
Peginterferon-alpha
Enemy: Viruses in general (??)
Target/MOA: Prevent protein synthesis directed by viral mRNA
What does that mean? The binding of interferon to specific cell surface receptor molecules signals the cell to produce a series of antiviral proteins. Keep in mind that the cell releases interferon on its own accord upon viral infection in the absence of the drug. The drug simply increases the amount of interferon in the body, thereby helping to amplify the anti-viral properties IFN already carries. IFN can inhibit translation of viral proteins or replication of viral genome.
Zanamivir and Oseltamivir
Enemy: Influenza A and B
Target/MOA: Potent and selective sialic acid analogue inhibitors; Permits release of influenza virus from infected cell, leading to aggregation of virus at the cell surface and reduced spread of virus within respiratory tract.
What does that mean? Sialic acid analogues can produce conformational changes in the active sites of Influenza A and B neuraminidases. A and B neuraminidases destroy sialic acid residues on the host, preventing recognition of said cell by viral hemaggluntinin. When loss of recognition occurs, release of the virus from the cell occurs.
Ribavirin and Trifluridine
Prevents “nucleic acid synthesis by other viruses” … and that is all of the information given.
Foscarnet
On the list of things we need to know…but cannot find info in packet.
