Antiviral Therapy (10) Flashcards
Are viruses sensitive to antibiotics?
No - viruses are insensitive to antibiotics
→antibiotics target common processes to bacteria
→ antivirals need to be much more specific than antibiotics
→ most antivirals target chronic, persistent or latent viral infections (for acute they need to be taken quickly)
→ an intact immune system is important for success in treating viral infections
What are the properties needed for antivirals?
- Specificity and potency in vitro → target enzyme without being toxic to host
- Good selective index in vitro→ 50% toxic conc/50% virus inhibitory conc
- Good therapeutic index in vivo→ minimum toxic dose/therapeutic dose
- Good oral bioavailability if possible → tablet or medicine highly absorbed into bloodstream, cheaper
Why is the therapeutic index different to the selective index?
Selective index is measured in vitro, while therapeutic index is measures in vivo
→ therapeutic index considers pharmacokinetics
What is pharmacokinetics?
The variation in the circulating blood concentration of a drug under a particular dose regime, influenced by ADME
Absorption → how well does the drug get into circulation? (depends on administration)
Distribution → does it get into the right tissues?
Metabolism → how quickly is it broken down in the body?
Excretion → how quickly is it excreted from the body?
→ all these factors influence how much drug will be about and how toxic it is to the animal
What is bioavailability?
The fraction of administered drug that makes it into the circulating blood stream
→ properties like acid stability and resistance to digestive enzymes is required
How are new compounds for antivirals discovered?
- High throughput screening of small molecules - random way of testing banks of small molecules
→ for virus growth inhibition in cell culture and enzyme inhibition in vitro - Molecule modelling - using known 3D structures of proteins, substrates, interactions to design inhibitors
→ need to be identifies, purified and crystal structure generated - Structure-acitivty relationships
→ modifications to enhance activity or pharmacokinetics of lead compounds
→ 1 and 2 discovery of potential lead compounds
What are the stages of drug development?
-
In vitro studies of antiviral effect and cytotoxicity
→ good selective index - Animal models for safety and activity
→ good therapeutic index - Clinical trials in humans - phases I to IV (10 years, £400M minimum)
What are the phases of human clinical trials?
Phase I → first-in-main trials - 40% fail
→ small number (10-50) healthy volunteers, single small dose increasing to higher multiple doses, monitor for adverse effects and pharmacokinetics (same in humans as in animals?)
Phase II → small number (50-100) PATIENTS - 30% fail
→ IIa - confirm metabolism is same as in healthy volunteers (e.g. changes to liver activity can affect)
→ IIb - compare with placebo for efficacy, usually double-blinded (modern day placebo not always used - compared to standard)
Phase III → large numbers (1000s) of patients - better statistical power, across 2/3 countries
→ randomised double-blind trials versus placebo and existing treatments
Phase IV → after approval for marketing, large scale, broader patients population
→ monitored for long term effectiveness and long term side effects, may test the drug in new age groups of patients types
What are some examples of antivirals against HIV
Nucleoside reverse transcriptase inhibitors
Non-nucleoside reverse transcriptase inhibitors
Protease inhibitors
Integrase inhibitors
Fusion inhibitors
Resistance and combination therapy
What are some targets for anti-HIV therapy?
Viral enzymes:
Reverse transcriptase → makes dsDNA copy of HIV RNA genome
Protease → cleaves Gag and Gag/Pol polyproteins into structural and enzymatic viral components
Integrase → catalyses insertion of dsDNA copy of viral genome into host cell chromosome
Viral processes:
Cell attachment and entry → HIV envelope proteins bind to cell surface receptors and cause membrane fusion (be careful not to inhibit cellular part)
What are nucleoside reverse transcriptase inhibitors (NRTIs)?
Bind the active site of RT preferentially, incorporated into viral DNA causing chain termination
Azidothymidine (AZT) was the first anti-HIV drug → thymidine analogue, 3C-OH replaced with N3
→ due to its azide group (instead of OH) it causes chain termination
What are next generation NRTIs?
Resistance developed against AZT → next-generation NRTIs (current front-line drugs), still analogues of base residues
Iamivudine → cytidine analogue, 3C-S
Emtricitabine → cytidine analogue
Abacavir → guanidine analogue
Tenofovir → adenosine analogue
What are non-nucleoside reverse transcriptase inhibitors (NNRTIs)?
Bind to an allosteric sit on RT (known as NNRTI pocket), diverse chemical structures
→ very specific, active against HIV-1 but not HIV-2
→ nevirapine (original), efavirenz (front-line), etravirone (new in 2008)
→ bin in non-competitive manner, binding causes conformational change in RT - can’t catalyse
What are protease inhibitors?
HIV protease cleavage site: Leu-Asn-Phe|Pro-Ile
Saquinavir (1995) → transition state analogue of the proteolytic cleavage reaction
→ blocks active site of protease - prevents actual substrate from getting in - blocks protease cleavage
Indiavir, atazanavir, fosamprenavir
What are integrase inhibitors?
Inhibitors strand transfer between the viral DNA ends and cellular DNA
→ first is Realtegravir (Oct 2007)
→ difficult regiment to follow - chosen if NRTI or protease inhibitors not working
