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23 Cards in this Set

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What is the basic pathway to discovering antiviral drugs?

How does cc, ec, and pk fit into it?
EC/CC - selectivity index
cc - cytotoxicity properites (want to be minimized)
ec - potency
pk - how the in vitro activity acts in vivo. Sometimes great in vitros can suck in vivo

May take years to develop a preclinical candidate.
What are the Guidelines for Advancing Drug Candidates through pre-clinical development?
Potent (EC50 < 1μM), and non-toxic antiviral activity;

Absorption, tissue distribution (if its an oral drug, must be able to cross gut epithelium), metabolic stability, and excretion (ADME) characteristics appropriate for achieving desired drug exposure levels in animals, preferably by oral administration;

Acceptable preliminary safety profile in animal studies; and

Protective efficacy in in vivo models of host viral disease.
What are the more common classes of antivirals that SIGA are trying to develop anti-virals against?
Small molecules - tactic is to try structural mimicry

Biologicals- including Antibodies, peptides, small interfering RNA, interferons.
What are five anti-viral mechanisms?
Binding and Entry Inhibitors
Integration Inhibitors
Replication Inhibitors
Egress Inhibitors
Protease Inhibitors - targets the long polypetides that will get cleaved into small functional units
How do genome replication inhibiting antiviral medications work? What do they look like, what do they interfere with?
Nucleoside analogs

Interfere with polymerase activity/processivity-resulting in incomplete replication of viral genomes (commonly referred to as “chain terminators”).

Resistance variants have decreased fitness in vivo, and resistance to one type of analog (e.g. thymidine) does not confer resistance to other types (e.g. guanosine).

Acyclovir (Zovirax®)-acyclic guanosine derivative
Valacyclovir (Valtrex®)-acyclovir prodrug (l-valyl ester) converted to acyclovir upon oral ingestion.
Zidovudine (Retrovir®) (AZT)-deoxythymidine analog
What is the mechanism of action of acyclovir?
Acyclovir is converted to acyclovir monophospate by the virus-encoded thymidine kinase

Subsequent conversions to diphosphorylated and triphosphorylated forms are carried out by cellular kinases.

The acyclovir triphosphate competes with 2-deoxyguanosine triphosphate (dGTP) as a substrate for the viral DNA polymerase.

Once bound by the polymerase, acyclovir triphosphate acts to terminate replication of the engaged DNA template.
What is chain termination?
The absense of a 3’OH in the incorporated ACV-TP prevents the formation of a 5’-3’ phosphodiester linkage essential for DNA chain elongation.

Because there is an interruption to the sugar chain, it terminates.
What are the difference between acyclovir vs valacyclovir?
Acyclovir is polar, hydrophilic, and thus dependant on poor passive diffusion and low capacity active transport (via endogenous nucleoside transporters) to permeate the intestinal epithelium. As a result, acyclovir is a drug with poor oral bioavailability (10-30% in humans).

Valacyclovir, the L-valyl ester PRODRUG of acyclovir is more lipophilic than acyclovir, with 3-5X better oral bioavailability (54%) than that of the parent compound due, in part, to the use of a carrier-mediated intestinal membrane transport system mediated by the membrane protein, PepT1. Hydrolysis of the L-valyl ester to form acyclovir is carried out by the cellular biphenyl hydrolase-like protein (BHLP).
What is oral bioavailability?
Oral Bioavailability: The amount (expressed as a % of input) of an
ingested drug absorbed through the gastrointestinal tract.
What is a prodrug?
Prodrug: Pharmacologically inactive derivative of a parent drug molecule that requires spontaneous or enzymatic transformation within the body to convert to the active drug molecule.

Valacycolvir is a prodrug of acyclovir that has poor oral availability.
For which stage(s) of HUMAN a-herpesvirus infection does acyclovir or valacyclovir provide therapy?
a) Primary lytic infection
b) Latent infection {if it's truly latent, there's no reason that acyclovir should work here}
c) Reactivation
d) Primary lytic infection and Reactivation
e) All of the above


I don't know what the answer is. Pretty sure he addressed why b wasn't...and therefore e isn't. After that: go with god.
Can you treat feline herpesvirus with valcyclovir?
Point: don't assume that all species will be effected similarly.

Valacyclovir is toxic when administered to cats experimentally infected with FHV.

Treated cats displayed bone marrow suppression, renal and hepatic toxicicity.

Instead, one option is the nucleoside inhibitor triflouridine (Viroptic®) for treatment of feline ocular herpesvirus infection (typically with corneal involvement).

The MOA is the same as that for acyclovir, but the compound is much better tolerated in cats at therapeutic doses.
What is zidovudine MOA used to treat?
Similar mechanism to that of acyclovir, but this time the affected
polymerase is reverse transcriptase (RT) rather than a viral DNA-dependant-
DNA polymerase (retrovirus v. dsDNA virus).
Considered a Nucleoside-Reverse Transcriptase Inhibitor (nRTI).
First FDA-approved drug against HIV.
Conversion of zidovudine to the triphosphorylated form is dependant on the
activity of the cellular thymidine kinases. Consequently, zidovudine acts as a
competitive inhibitor of the cellular thymidylate kinases.
Currently available are the following nRTI’s with superior efficacy to that of zifovudine:
Emtracitabine (Tenofovir®)
Lamivudine (Abacavir®)
What are nRTI v NNRTI?
nuclease and non-nuclease RTI?
How do NNRTI's work (Non-Nucleotide Reverse Transcriptase Inhibitors)?
Unlike nRTI’s, bioactivation is not required for activity of this drug.
These compounds binds RT at a site distinct from the polymerase
catalytic site.
Binding induces a conformational change that essentially inactivates RT
Single drug therapy regimens using these compounds led to
relatively rapid emergence of resistant viruses in vivo.
Resistance to one of these drugs generally confers resistance to
other drugs in this class.
This drug has proven to be more efficacious when used in
combination with nRTI’s as well as other classes of HIV antivirals.

Etravirine
Approved in 2008
Effective against NNRTI resistant viruses
How do protease inhibitor medications work?
Prevent processing of the Gag and Gag-Pol polyprotein
precursors, resulting in the release of noninfectious virions
from infected cells.

Lopinavir
Atazanavir
Fosamprenavir
Darunavir
Saquinavir
What do combination therapies target?
Due to the emergence of resistant variants following treatment with any single drug from a given class, a combination therapy approach has been adopted in the treatment of HIV infection.

Typically, treatment is initiated with either a combination of one PI and two nRTIs or one NNTRI and two nRTIs.

Treatment experienced patients with resistant variants onboard can now be treated with either of two recently introduced classes of antiviral (HIV fusion/entry inhibitors or a viral integrase inhibitor)
How do viral entry inhibitor drugs work?
Block the binding, fusion, or entry of viruses into susceptible cells.


Enfuvirtide-HIV- fusion inhibitor
injectable only.
Maraviroc-HIV-CCR5 co-receptor
antagonist-therefore
only efficacious against
CCR5 tropic HIV-1.
Razivibumab-RSV-monoclonal Ab
ST-193-Lassa fever virus entry
inhibitor.
How do viral integrase inhibitor viral drugs work?
Raltegravir

Inhibits the function of the virally encoded integrase protein, responsible for insertion of the retroviral genome into the genome of the host.
Integration is a required step in the replication cycle of the virus.
Used principally for patients in whom available antiretroviral agents have failed to achieve HIV suppression.
How do egress inhibitor viral drugs work?
Block the exit of infectious virus from infected cells
ST-246-smallpox antiviral interacts with virally encoded protein F13L, a protein required for the formation of mature virions involved in dissemination of infection in the host.
Gleevec inhibits Abl family protein kinases required for formation of actin tails at the site of poxvirus budding from infected cells.

Rational design of sialic acid receptor structural mimics to bind influenza virus neuraminidase protein and inhibit neuraminidase activity.
Binding of the neuraminidase by this class of inhibitors (oseltamivir or zanamivir) blocks release of virions from infected cells.
Slowing of virus dissemination results in changes in some aspects of viral pathogenesis, allowing more time for development of a pathogen specific immune response.
How does interferon treatment of viral drugs work?
Interferons are a central component of the host innate immune response to infection or colonization by foreign pathogens. Commonly employed interferons are alpha, beta, and gamma forms.

Use of pegylated interferon alpha and ribavirin (a nucleoside analog) in combination is a standard therapy for treatment of chronic HCV infection in humans.

Interferon inhibits translation of HCV by blocking viral protein synthesis and degradation of viral RNA by interferon induced gene products.

Following treatment with interferon, there is a failure to form polyribosomes on the IRES(Internal Ribosome Entry Site) contained within the 5’UTR of the viral genome.
Summary of antiviral agents
Similar antiviral discovery and development strategies can be employed for therapies against a wide diversity of viruses (e.g. nucleoside analogs).
Drug properties (PK,toxicology) are species specific.
The regimen of antiviral treatment must be designed to maximize drug efficacy while minimizing selection of drug resistant virus variants.
How do you inhibit virus replication using complementary nucleic acid?
There was another pic that might be better on page 22.