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Flashcards in 08 Anti-Viral Agents Louie Deck (41):

What are the Viral Entry Inhibitors currently available?

EnFuvirtide (CD4 blocker). Maraviroc (CCR5 Antagonist)


What is the problem with monotherapy of EnFuvirtide for HIV?

Very quick resistance occurs


How does Maraviroc (Selzentry) work?

Competitively binds to CCR5, preventing an interaction with GP120. It is a "chemokine receptor antagonist"


What is Maraviroc (Selzentry) indicated for?

Indicated for treatment-experienced adult patients infected with only CCR5-tropic HIV-1 detectable, who have evidence of viral replication and HIV-1 strains resistant to multiple antiretroviral agents


What is Ibalizumab?

A novel humanized monoclonal antibody (Mab) binding to a conformational epitope on CD4, blocking entry to HIV-1. In Phase II right now


What did the IV Ibalizumab Phase 2b study results show?

Favorable data indicating efficacy and drug will continue in development


What are the NRTIs that are Dideoxynucleoside Analogs?

Stavudine. Lamivudine. Didanosine. Zidovudine. Emtricitabine. Abacavir. On all of these, the 3' Hydroxyl group is important for elongation


What are the steps in Intracellular Transport of Nucleosides?

Dideoxy Nucleoside (ddN) is brought in through a channel (ENT2). Once inside, it interacts with kinase to become ddN-TP. This can then either bind to RT (termination of vDNA), go into the mitochondria (causes toxicity, Lactic Acidemia), or go into the Nucleus


How do cells get ride of ddN?

Once converted to ddN-MP it can actually get pumped out by the MRP-2, -4, or -5 pumps


Why is Nucleoside therapy for Men and Women different?

The ENT2 transporter is also used for folic acid, so there are more of them in women. This causes women to have more ADRs, but also better remission rates


What is the benefit of Acyclic Nucleoside Analogs?

No ribose ring, avoids enzymes that cleave them, longer T1/2


What are some of the Acyclic Nucleoside Analogs?

Acyclovir. Ganciclovir. Penciclovir. Cidovovir, Adefovir, Tenofovir


Which Acyclic Nucleoside Analogs come with a phosphate group already attached?

Cidofovir. Adefovir. Tenofovir. This phosphate group causes them to be highly renally toxic, can also lead to osteoporosis (since calcium will be excreted along with the phosphate group)


What is Ganciclovir used for?

CMV. Active against herpes viruses but especially cytomegalovirus (CMV) infections, which typically cause retinitis, and may cause pneumonia, colitis, esophagitis, and hepatitis in immunocompromised patients


What is Cidofovir used for?

Synthetic acyclic purine nucleotide analog of cytosine nucleoside when phosphorylated to the diphosphate, inhibits CMV DNA polymerase and blocking viral replication. Disphosphate has 2-3d T1/2. Indicated for treatment of CMV retinitis


What are the NNRTIs used?

Delavirdine. Efavirenz. Etravine. Nevirapine


Which NNRTI is a potent CYP3A INHIBITOR?

Delavirdine. All others are inducers


What is a common ADR with all NNRTIs?



Which NNRTIs cause Hepatotoxicity?

Efavirenz. Etravine. Nevirapine. The only one that doesn't is Delavirdine


What is the 2nd Gen NNRTI?

Etravirine. Resistance to other NNRTIs does not seem to confer resistance to Etravirine. Etravirine, in combination therapy, is indicated for the treatment of HIV Type 1


Rilpivirine is a new NNRTI being looked at, why is it dosed 25mg in study results?

At 100mg/day it started showing signs of QT Prolongation


What are the Protease Inhibitors used?

Indinavir. Sawuinavir. Ritonavir. Nelfinavir. Indinavir. Atazanavir


What does the inhibition of Integrase cause?

Strand Transfer Shifts the fate of HIV-1 DNA resulting in an irreversible block to infection. Dead-end products = cell death


What are the Integrase Inhibitors in advanced clinical developed?

Raltegravir. Elvitegravir


What did a trial conclude when looking at the effect of Dolutegravir on actual GFR and CrCl in healthy subjects?

DTG has no effect on actual GFR. DTG decreases eGFR and CrCl via effect on proximal renal tubular excretion of creatinine, similar to cobicistat


What is the goal of Zinc Finger Gene Therapy?

Create a modification to CCR5 co-receptor. Persons with the delta 32 deletion of CCR5 are highly resistant to HIV infection. Zinc Finger Nucleases (ZFNs) are "designer restriction endonucleases" which cleave an area between two CCR5 binding domains. This in turn introduces a DNA break that causes permanent CCR5 co-receptor modification in target cells


What is Amantadine (Symmetrel)?

Prevention/treatment of Influenza A Virus (not B). Prevention has efficacy of ~70%. CNS effects limit wide use


What is the MOA of Amantadine?

It appears to be VIRUSTATIC by preventing uncoating of virus particles, leading to no viral replication and no infection (ideally). It affects maturation of Influenza HA Glycoprotein in trans-Golgi network


What is Rimantadine?

Same as Amantadine, but with fewer ADRs


What do Neuraminidase Inhibitors do?

Neurominidase breaks the bond that holds new virus particles to the outside of an infected cell by cleaving sialic acid from the cell surface. This releases new viruses that can infect other cells and spread infection. Neuraminidase inhibitors prevent viral cleavage of sialic acid preventing new virus particles from being released, thereby limiting the spread of infection


What are the Neuraminidase inhibitors used?

Oseltamivir and Zanamivir


What are the common drugs used for HCV?

PegIFN and RBV


How is PegIFN dosed for HCV?

1.5ug/kg weekly


What is the range that RBV is dosed for HCV?

800-1400mg daily


What are the difference classes of Interferons?

a, B, and y. Each distinct. Different producer cells, inducers, and biologic effects. IFN-a and -B are produced by nearly all cells in response to invasion. Only INF-a has been approved for viral treatment. IFN-y only produced by T cells and NK cells


What is the MOA of IFN?

Induces changes in the infected or exposed cell to promote resistance to the virus. Induces several enzyme activities that promote an antiviral state


Peginterferons vs. Interferons, what is the rationale for pegylation?

Reduces rate of absorption and clearance. Lower immunogenicity. Maintains higher steady state --> increased viral response


What is Ribavirin?

Active against many DNA/RNA viruses and highly active against influenza A and B, but is only approved for treating RSV in infants and young children by aerosol and Hep C together with interferon


What are the characteristics of the new target: NS3 Protease?

Hepatitis C RNA encodes for a polyprotein that is 3,000 AA long. This is cleaved by viral and host proteases to form structural and nonstructural proteins. The Nonstructural (NS) proteins are further processed by two viral proteases, NS2/3 and NS3


What are the two types of NS3 Protease Inhibitors?

a-Ketoamides (form a reversible covalent bond with serine in the active site). Competitive, noncovalent inhibitors (aim to bind more strongly to active site than substrate through noncovalent interactions)


What is needed for NS3 Protease to be active?

In order to be activated it must be bound to an NS4a cofactor