Antiviral Drugs Flashcards
How are viruses classified?
- Type and structure of nucleic acid and the strategy of its replication.
- Symmetry of capsid.
- Presence or absence of lipid membrane
What are the stages un viral life cycle?
1) Attachment
2) Penetration
3) Disassembly (release of viral genome),
4) Transcription
5) Translation
6) Replication
7) Assembly
8) Release
Name and describe the three mechanisms of antivirals
Virucides - These directly inactivate viruses eg, detergents, UV light, cryotherapy.
Antivirals - Inhibit replication at cellular level but therefore aren’t effective in elimination of nonreplicating viruses.
Immunomodulators - Replace deficient host response or enhance endogenous response
Describe some of the targets for antiviral drugs
- Entry inhibition,
- Viral disassembly,
- Viral replication (Viral polymerases, viral proteases, integrase),
- Viral release inhibitors
What is the function of nucleotide analogues?
The competitively inhibit the action of viral polymerase which inhibits new viral DNA production
Describe features of retroviruses
- Positive sense single stranded RNA virus.
- Need for reverse transcriptase to make DNA copy of viral RNA. The DNA copy is then integrated into the genome of host cell and terminated as provirus. The provirus DNA is then transcribed into new genomic RNA and mRNA for translation into viral proteins.
Describe the process of HIV entry
It is mediated by envelope glycoprotein spike (mainly gp120) which binds to a CD4 receptor and one of the two co-receptors CCR5 or CXCR4
What is the significance of CCR5 co-receptor
A mutation in this receptor has resulted in HIV being unable to bind to cells. Therefore this is a good target for treatment.
Give examples of entry inhibitors
- Fusion inhibitors eg, Enfurvitide (T20) (not used often as it is toxic) prevents the viral cells from fusing with host cell and releasing viral genome.
- CCR5 antagonists, eg, Maraviroc
What are the two reverse transcriptase inhibitors?
- Reverse transcriptase inhibitor .
- Non-Nucleoside reverse transcriptase inhibitors
Name some drugs in the nucleotide reverse transcriptase inhibitors (NRTIs) and their side effects
Abacavir (analogue of guanosine) - SE = ischaemic heart disease
Tenofovir (Analogue of adenosine) - SE = Decreased bone mass density, osteomalacia, increased fracture risk
(Emtricitabine and lamivudine)
NRTIs are prodrugs, what is needed to activate them?
Phosphorylation by viral and/or cellular kinase.
Name two examples of NNRTIs
Efavirenz
Rilpivirine
Both drugs can cause neurological and psychiatric AE.
Describe the mechanism of HIV protease inhibitors
Virus specific protease gives rise to various functional proteins and since the protease doesn’t exist in host it is selective.
Name some examples of protease inhibitors and their side effects
Darunavir (ischaemic heart disease and nephrolithiasis) , Atazanavir (nephrolithiasis)
What is the mechanism of integrase inhibitors
Inhibit HIV integrase activity:
- 3’ end processing of double stranded viral DNA
- Strand transfer which joins viral DNA to host chromosomal DNA forming a provirus
Name an example of an integrase inhibitor and its side effects
Dolutegravir - weight gain, depression and suicidal ideation
What is HAART?
Combination therapy - typically 2 NRTIs and an additional drug from another class
Describe how RNA viruses are classified?
Positive-sense viral RNA (can be imnmediately translated by host cell)
Negative-sense viral RNA - must be concerted to positive-sense by RNA dependant RNA polymerase.
What are the three types of RNA genome?
dsRNA (double stranded), +ssRNA and -ssRNA. (+/- single stranded)
Describe features of hepatitis C virus
Positive-sense single stranded RNA virus which can cause acute and chronic hepatitis, cirrhosis and hepatocellular carcinoma.
Name targets of HCV treatment and examples of drugs.
NS3 - Protease inhibitors, eg, simeprevir and grazorprevir.
NS5A - NS5A inhibitors eg, ledipasvir and elbasvir.
NS5B - Nucleotide inhibitors and non-nucleoside inhibitors eg, Sofosbuvir and Dasabuvir
Describe features of Influenza
(Orthomyxoviridae). There are 3 types; A,B and C. They are enveloped negative-sense single stranded RNA virus.
What is the function of neuraminidase inhibitors in the treatment for influenza
Prevents the release of new viral cells
Describe the mechanisms of another influenza antiviral treatments.
Amantadine/rimantadine - They block the M2 ion channel. (Concentrated in lysosomes0
Baloxavir - inhibits viral mRNA replication
What are the functions of the M2 ion channel
- Virion uncoating following entry by endocytosis and
- Maturation of viral envelope proteins during virus assembly and release.
Describe features of DNA viruses?
They use cellular enzymes for transcription and replication of their genome. Early mRNA transcripts = regulatory proteins and proteins for DNA replication. Late = structural proteins. eg, herpes simplex virus, human papilloma virus, Varicella zoster and hepatitis B virus.
What is the mechanism and uses of Aciclovir
Deoxyguanosine analogue which competitively inhibits viral DNA polymerase. It is used in the treatment herpes simplex virus and varicella zoaster virus infections
What are some other herpesvirus antivirals?
Valaciclovir - prodrug of aciclovir (higher oral bioavailability).
Ganciclovir - Deoxyguanosine analogue. It is an inhibitor of CMV replication.
Foscarnet - Directly inhibits herpesvirus DNA polymerase or HIV RT.
describe some features of the hepatitis B virus
- Enveloped, dsDNA virus which causes acute and chronic hepatitis, cirrhosis and hepatocellular carcinoma.
Describe the treatment of chronic HBV
Immunomodulatory using pegylated interferon alpha.
Nucleotide therapies - these are agents active against reverse transcriptase eg, tenofovir and entecavir.
What is the development of resistance favoured by?
High viral load, High intrinsic viral mutation rate, degree of selective drug pressure and antiviral target that can mutate without affecting fitness.
