Antiviral drugs Flashcards
(36 cards)
Latent stage
: virus is integrated into host genome. Non-replication of
virus. Can be non-integrated as well.
Virus structure:
Lipoprotein envelope, nucleic acid core, coat (capsid), Coat and nucleic acid core make up nucleocapsid, capsomere (morphological protein units that make up the coat. Some viruses take a portion of the cellular membrane with them as they leave, giving them a protective
envelope. This can help them survive longer outside of the cell.
Main Approaches for Stopping Viral Replication
- Block virus attachment to cells.
- Block uncoating of the virus.
- Inhibit viral DNA or RNA synthesis.
- Inhibit specific viral protein synthesis.
- Inhibit viral assembly.
- Inhibit virus release from the cells.
- Stimulate host immune system.
What can be used to stop virus attachment?
Viruses have an attachment phase where they recognize a protein on the cell surface. If you can make a protein that mimics the viral attachment protein thats needed for attachment, you could outcompete with the viral protein for attachment. Viruses are usually at really high titer though, so its hard to outcompete them. These cell surface markers usually
have a purpose that is utilized by the cell (cell recognition), so blocking these can potentially block an essential function of the cell.
Characteristics of Influenza A Virus
- Primarily found in birds
- Some strains infect humans and other animals
- Source of all human flu pandemics
- Segmented ssRNA genome
- H=hemagglutinin
- N=neuraminadase
- H and N give the knob appearances. - In many cases with influenza, humans are secondary hosts. Pandemic is an epidemic that extends beyond one region of the world.
Influenza virus life cycle
Influenza virus life cycle: Attachment via knobs of hemagglutinin which binds to cell surface proteins, this stimulates the endocytosis process within the cell. the primary cells infected are those that line the respiratory tract. This is a non-envelope virus particle, but it does acquire a membrane during the
endocytosis process. It gets uncoated, and then the RNA gets transferred into the nucleus (unique) where it then undergoes splicingand rounds of RNA replication occur through RNA polymerase which makes viral mRNAs
that subsequently get translated as well as others that become enitre RNA molecules that become the genome.Some of the viral proteins get transferred to the membrane via the golgi, which then get expressed on the cell surface. The virus can then bud off and pick up the proteins to incorporate them into its capsid.
Key Influenza Virus Proteins
HA, NA, M1, M2. M1 and M2 proteins are found internally in the capsid.
Virus Uncoating and Amantadine
- M2 is an ion channel located in the lipoprotein coat that forms the exterior shell of influenza virus
- M2 protein allows H+ to enter the virus, promoting dissociation of M1 from the viral RNA. This step is required for the uncoating process that releases viral RNA into the host cytoplasm
- MOA: Blocks M2 ion channels inhibiting uncoating.
- Many strains of influenza A are currently resistant to this drug. In 2009 the CDC recommended use of neuraminidase inhibitors as the primary line of treatment of influenza due to the resistance problem associated with amantadine.
- Second action discovered accidentally: Amantadine stimulates dopamine release in mild Parkinson’s disease.- Virus remains trapped in capsid inside the cell. Drug was overused to
treat birds that were infected, and as a result resistance developed. - amantadine is highly specific for influenza A.
Adverse Affects of Amantidine
- Associated with increased anxiety and insomnia (likely due to its ability to stimulate norepinephrine release in the CNS)
- May exacerbate preexisting psychotic behavior or tendency toward epileptic seizures.-These are fairly minor issues if being used to treat for viral infection because its only given for about 10 days.
Challenges of antiviral therapy
- Viruse utilizes multiple host processes, so it is difficult to selectively
target the virus without harming the host. - Viruses often hide in the host cells by integrating their genome with
that of the host. There can be latency periods following the initial viral infection.
Most viruses: utilize host polymerases, ribosomes, tRNAs, post translational mods. Not all though.
Neuraminidase & Virus Budding
- Influenza virus release is initiated by virus attachment via hemaglutinin molecules in the virus envelope to sialic acid residues on the inner side of the plasma membrane.
- Neuraminidase molecules located on the influenza virus envelope cleave sialic acids.-Silaic acid cleavage is required for virus budding.
- Small molecule neuraminidase inhibitors have been used to prevent budding
Oseltamivir (Tamiflu)
- Orally available; a pro-drug. Only becomes functional in virus infected cells.- MOA:Neuraminidase inhibitor (effective against influenza A and B). Basically a competitive inhibitor of sialyic acid.
- Inhibits viral replication by preventing viruses from detaching and attacking other cells-useful only early in infection; can shorten the duration of infection
- Once too many cells are infected, this treatment won’t work well, so used only for early infections.
- Tamiflu can treat both influenza A and B.
Herpes Simplex Virus Family
- HSV-I&2
- Varicella zoster
-dsDNA genome
-Encodes own DNA polymerase: Potentiall drugable.
-Latent phase-no viral protein synthesis; virus hides in neurons
-HSV-8:Kaposis’s Sarcoma: Prior to HIV, this was almost a completely unheard of disease in humans. Only when the patient is immunosuppressed does HSV-8 become pathogenic. - HSV viruses tend to settle in neurons, which arent usually dividing. So they have low levels of expression of their polymerases, which explains why HSV viruses need to
have their own polymerases available.
What’s an interesting aspect of nucleus migration regarding herpes viridae?
In most DNA viruses, the DNA has to be transported into the nucleus via nuclear pores, butwith herpes the whole virus infects the nucleus where it is then uncoated. Viral DNA is then made using viral DNA pol, and then the host RNA pol is used to make RNA.
Acyclovir
- A guanosine nucleoside analog prodrug that is activated by Herpes Simplex Virus (HSV) thymidine kinase
- MOA: Chain terminator (suicide substrate). Inhibition of viral DNA pol and is a chain terminator.
- Used to treat Herpes simplex (1 and 2) and Varicella zoster (chicken pox and shingles) infections
- Has a 30 fold better affinity for viral polymerase.
- Can be incorporated into host DNA to some extent, but since its only active in infected cells, its ok to get rid of those cells. One of the safest drugs of all, no really serious side effects. Its a produrg given as a nucleoside and can only be turned into a nucleotide by HSV thymidine kinase
- Not as effective in karposis’s sarcoma virus infection because
the symptoms appear too late.
Why give a nucleoside rather than a nucleotide?
Nucleotides are phosphorylated,so they have a negative charge. This will cause the drug to be repelled by the cell surface (net negative charged). Nucleosides can be recognized by cell surface transporters. Host enzymes can add additional phosphates after HSV thymidine kinase adds the first phosphate. It lacks the 2 prime hydroxyl which prevents elongation.
HIV Latent period:
Latent period is one of the biggest problems with treating HIV. Very little virus detectable.Virus is integrated into cells including in T-helper cells. Asa result of the very low level of viremia
(level of virus dividing). There starts to be a decline in C4+T-Helper cells. Its only when the level of cells drops really low that the symptoms start to develop. Another population of cells that are affected are macrophages. Virus hides out in these as well during the latent period. When drug therapy eliminates the population of the active virus, there is almost always some left over in the macrophages that leads to reappearance of the disease.
HIV Replication Cycle:
-Believed to have originated in non-human primates. - Most AIDS is caused by HIV-1. - HIV utilizes reverse transcriptase. - T-helper
cells are the main regulator cells of the immune system and are responsible for activating other cells of the immune system.
Surface peptides on T-Helper cells and Macrophages
T-Helper cells—>CD-4—>CXCR4
Macrophages—>CXR5
Direction of replication of HIV genome
ssRNA—> RNA-DNA hybrid—> dsDNA —> Host genome
AZT/Zidovudine
- Pro-drug- must be phosphorylated to the trinucleotide level to be active
- MOA:HIV reverse transcriptase inhibiter and
chain terminator. Suicide substrate. - Highly toxic. Side effects include skin rashes, nausea, anemia, neutropenia, liver damage, pancreatitis, lipodistrophy
- Resistance develops rapidly (discussed later in relation to drug resistance mechanisms)-Nucleoside analog of thymine. Azide at the 3 prime position where there would normally be a hydroxyl group.
AZT/ Zidovudine Nonspecificity:
Because it is not totally specific to reverse transcriptase, it comes with someside effects when its given alone. If it is given alone it needs to be given at high dosage to be effective. It will start to inhibit cellular polymerases which gives rise to side effects. Bone marrow gets affected when you start to inhibit polymerases,hence the anemia. Elevated blood cholesterol (lipodistrophy) occurs as well.A combination of drugs is given to try to avoid resistance developing. Viral diseases are especially suceptible to develop drug resistance mainly because: they have a rapid generation
time and their reverse transcriptases are very error prone which gives rise to many mutations.
Nevirapine
- Developed in response to nucleoside inhibitor drug resistant strains of HIV-1
- MOA: Non-nucleoside reverse transcriptase inhibitor (non competitive).
- Side effects similar to AZT.- Allosteric reverse transcriptase inhibitor. Doesnt really resemble a nucleotide at all, which makes sense because it is not competingwith nucleotides. It can still inhibit other polymerases so its side effects are similar to AZT and other competitive nucleoside inhibitors. Two strains of HIV known to cause human diseases: HIV-1 and HIV-2, which are very similar. The reverse transcriptase of HIV-2 has a slightly different amino acid sequence at the point where this drug would normally bind and inhibit, so this drug cannot inhibit HIV-2.
Indinaivir
- Most effective class of drugs for treating HIV- 1 infection
- MOA: HIV-1 protease inhibitor.
- Side effects similar to AZT. Also kidney stones.
- Instead of targeting the reverse transcriptase, it targets a protease
encoded by the virus. Some of the proteins made by the virus
are initially expressed at a pro-protein that requires cleavage to
become active. This drug inhibits a protease that is responsible for making
this cleavage. Found to be more effective than directly targeting the reverse transcriptase.
