L14 - Antiviral drug discovery Flashcards
Intended Learning Outcomes • Being able to explain the fundamental principles of antiviral drug discovery and validation. • Knowing the main antiviral drug discovery pipelines. • Being able to describe key antiviral mechanisms. • Being familiar with major breakthroughs in antiviral treatment and their impact on public health. • Being aware of challenges in antiviral treatment, such as drug resistance, toxicity, and effective (92 cards)
1
Q
What are antiviral drugs?
A
Medications designed to inhibit viral replication by targeting specific stages of the viral life cycle.
2
Q
What is the difference between broad-spectrum and specific antivirals?
A
Broad-spectrum antivirals target multiple viruses, while specific antivirals target a single virus.
3
Q
How do entry inhibitors work?
A
They block viral attachment or fusion with the host cell.
4
Q
What do polymerase inhibitors do?
A
They prevent viral genome replication by inhibiting RNA/DNA polymerases.
5
Q
How do protease inhibitors work?
A
They prevent viral protein maturation.
6
Q
What are immunomodulators?
A
Drugs that enhance the host immune response against the virus.
7
Q
Who proposed the “magic bullet” concept and what does it mean?
A
Paul Ehrlich in the early 1900s, suggesting drugs could selectively target pathogens without harming the host.
8
Q
What was the first approved antiviral drug and for what disease?
A
Idoxuridine in 1962, for Herpes Simplex Keratitis.
9
Q
What breakthrough treatment achieved a 95% cure rate for Hepatitis C?
A
Direct-acting antivirals (DAAs).
10
Q
How do neuraminidase inhibitors like oseltamivir (Tamiflu) treat influenza?
A
By blocking viral release from infected cells.
11
Q
What are the three UK-approved antivirals for SARS-CoV-2?
A
Remdesivir, Molnupiravir, and Nirmatrelvir/Ritonavir.
12
Q
What are the main challenges in antiviral drug development?
A
Drug resistance, delivery issues, toxicity, and treatment timing.
13
Q
How can AI contribute to antiviral drug discovery?
A
By accelerating compound screening and design.
14
Q
Why are monoclonal antibodies promising for viral infections?
A
They provide highly specific neutralization with immediate therapeutic effects.
15
Q
For how many viruses are antiviral therapies approved?
A
Less than 10 viruses.
16
Q
Which virus has the most approved antiviral drugs?
A
HIV, with over 50 approved antiviral therapies.
17
Q
How many antivirals are approved for SARS-CoV-2?
A
Approximately 2.
18
Q
At what stages do antiviral drugs act?
A
Entry, genome replication, protein processing, viral release, and immune modulation.
19
Q
What type of inhibitors block viral entry into host cells?
A
Entry inhibitors.
20
Q
Which inhibitors prevent viruses from leaving infected cells?
A
Neuraminidase inhibitors.
21
Q
How do reverse transcriptase inhibitors work?
A
They block reverse transcription in retroviruses like HIV.
22
Q
What led to increased antiviral development in the 1960s and 1970s?
A
The success of antibiotics and improved understanding of virus replication.
23
Q
What was the initial method for antiviral drug discovery?
A
“Blind screening” – testing random chemicals for antiviral activity in cell cultures.
24
Q
What is the purpose of lead modification in drug development?
A
To reduce toxicity, increase solubility, and improve bioavailability.
25
How much does it cost to develop a new antiviral drug?
Around £1.3 billion.
26
How long does it take to develop an antiviral drug?
10–12 years.
27
What are the key steps in the drug discovery process?
Target identification, screening, lead optimization, preclinical testing, and clinical trials.
28
What is the difference between mechanism-based and cell-based screening?
Mechanism-based screening targets specific enzymes or receptors, while cell-based screening examines the effect on viral function in cells.
29
What is high-throughput screening?
An automated method that tests thousands of compounds per day for antiviral activity.
30
Where do the compounds from high-throughput screening come from?
Company-owned or national compound libraries.
31
What does structure-based drug design require?
The atomic structure of the target molecule and an understanding of its mechanism of action.
32
How does structure-based design improve drug development?
It allows the creation of ligands that bind to and inhibit specific viral targets.
33
Give an example of structure-based design in antivirals.
The development of HIV-1 protease inhibitors like Saquinavir.
34
What was the first FDA-approved antiretroviral drug for HIV?
AZT (zidovudine) in 1987.
35
Does ART cure HIV?
No, but it turns HIV into a manageable chronic condition.
36
What was the initial (old) treatment for HCV?
Interferon and ribavirin, which had low cure rates and severe side effects.
37
Why are DAAs a major breakthrough?
They have fewer side effects and offer a realistic path toward HCV eradication.
38
What is the primary target of DAAs?
HCV proteins involved in replication and assembly.
39
Why are DAAs more effective than interferon-based treatments?
They directly inhibit viral components rather than relying on immune stimulation.
40
What advantage do DAAs offer over previous treatments?
Higher cure rates, shorter treatment duration, and fewer side effects.
41
What are subgenomic replicon RNAs?
Artificially transcribed viral RNA that allows for studying HCV replication in vitro.
42
Why are Huh-7 cells used in HCV research?
They support the replication of HCV subgenomic replicons.
43
What is the significance of stable HCV replicon cell clones?
They enable long-term studies of viral replication and drug testing.
44
What complications can chronic HBV infection cause?
Cirrhosis, liver failure, and hepatocellular carcinoma.
45
What was the first approved therapy for HBV?
Interferon-alpha, which has low success rates and severe side effects.
46
What are nucleos(t)ide analogues (NAs)?
Drugs like tenofovir and entecavir that inhibit HBV reverse transcription but do not cure the infection.
47
Why do HBV and HIV treatments overlap?
Both viruses use reverse transcription, making some drugs effective against both.
48
Which HIV drug is also used for HBV treatment?
Tenofovir.
49
What new HBV treatment strategies are under investigation?
RNA interference, CRISPR-based therapies, and immune modulators.
50
What do cap-dependent endonuclease inhibitors do?
They prevent viral mRNA synthesis, stopping replication early.
51
What type of virus is SARS-CoV-2?
A positive-sense, single-stranded RNA virus.
52
What are the three main antivirals approved for SARS-CoV-2 in the UK?
Remdesivir, Molnupiravir, and Nirmatrelvir/Ritonavir.
53
How does Remdesivir work?
It is a nucleoside analogue that competes with natural nucleotides to disrupt viral RNA replication.
54
What is the only broad-spectrum antiviral in clinical use?
Ribavirin.
55
How does Ribavirin work?
It mimics adenosine and guanine nucleosides, disrupting viral replication.
56
Why are broad-spectrum antivirals challenging to develop?
They must balance effectiveness against multiple viruses while minimizing host toxicity.
57
Why do viruses develop drug resistance quickly?
Many viruses, especially RNA viruses, have high mutation rates.
58
How can resistance be reduced?
By using combination therapies that target multiple viral pathways.
59
Why is monotherapy less effective?
It increases the likelihood of resistance development.
60
What are monoclonal antibodies used for?
They provide targeted neutralization of viruses like Ebola and SARS-CoV-2.
61
How is AI improving antiviral drug discovery?
Machine learning accelerates drug screening and optimization.
62
What is personalized medicine in antiviral treatment?
Tailoring therapy based on a patient’s immune response and viral strain.
63
What is the treatment for Ebola?
Monoclonal antibodies dramatically improve survival
64
How do antiviral drugs differ from antibiotics?
Antiviral drugs inhibit viral replication at various stages but do not directly destroy viruses, unlike antibiotics, which target bacteria.
65
Why is there a need for multiple antiviral drugs against the same virus?
Viruses, especially RNA viruses, have high mutation rates, leading to rapid resistance development, making multiple drugs targeting different stages of the viral life cycle essential.
66
What are entry inhibitors, and how do they work?
Entry inhibitors prevent viruses from entering host cells, blocking infection at the earliest stage.
67
What is the function of genome replication inhibitors in antiviral therapy?
They target viral polymerases or reverse transcriptases, preventing the virus from replicating its genome.
68
How do integrase inhibitors combat viral infections?
They block the integration of viral DNA into the host genome, preventing the virus from establishing a persistent infection.
69
What role do immune modulators play in antiviral treatment?
They enhance the host's immune response to help fight viral infections more effectively.
70
What are the key stages of antiviral drug discovery?
Target identification, in vitro testing, in vivo testing, and clinical trials.
71
Why is high-throughput screening important in antiviral drug discovery?
It allows rapid testing of large compound libraries to identify potential antiviral candidates efficiently.
72
What is mechanism-based screening in antiviral drug development?
It focuses on assessing specific effects on viral targets, such as protease activity, to identify effective drug candidates.
73
How did combination antiretroviral therapy (cART) change HIV treatment?
It transformed HIV into a manageable condition by using multiple drugs to suppress viral replication and reduce resistance.
74
What was the major breakthrough in hepatitis C treatment?
The shift from interferon-based therapies to direct-acting antivirals (DAAs), which achieved over 95% cure rates.
75
What is the current main treatment strategy for hepatitis B?
Nucleoside analogues, though research is ongoing to develop curative therapies.
76
When and why must influenza antivirals be given early?
They are most effective within 48 hours of symptom onset, as they prevent viral particle release early in the infection.
77
What antiviral drug strategies were developed for SARS-CoV-2?
Protease and polymerase inhibitors were rapidly developed and approved during the COVID-19 pandemic.
78
Why is drug resistance a major challenge in antiviral therapy?
Resistant variants can emerge quickly, especially in chronic infections, reducing drug effectiveness.
79
How might AI-driven drug design impact antiviral discovery?
AI could accelerate the identification of new antiviral compounds and improve drug optimisation.
80
What is the role of personalised medicine in future antiviral treatments?
It aims to tailor antiviral therapies based on individual genetic profiles to enhance effectiveness.
81
Why is continued research essential in antiviral drug discovery?
New viral threats constantly emerge, requiring novel and effective antiviral strategies.
82
What is the difference between in vivo, in vitro, and in silico experiments and benefits?
In vivo: Studies conducted inside a living organism (e.g. animal models, human trials). Reflects complex biological systems but can be ethically and technically challenging.
In vitro: Studies performed outside a living organism, in controlled environments like test tubes or culture dishes (e.g. cell cultures). Allows precise control but may not fully represent in vivo biology.
In silico: Experiments conducted using computer simulations or computational models (e.g. protein structure prediction, RNA-Seq analysis pipelines). Fast, cost-effective, and good for hypothesis generation, but requires validation through wet-lab methods.
83
What makes viral drug targets 'druggable'?
Druggable targets are typically viral proteins essential to the virus life cycle, structurally conserved, and accessible to small-molecule inhibition without affecting host proteins.
84
What is the significance of conserved viral protein structures for drug development?
Conserved structures allow broad-spectrum antivirals to target essential viral functions across different viral strains or species.
85
How does resistance to polymerase inhibitors typically arise?
Through point mutations in the viral polymerase gene that reduce drug binding while preserving enzymatic function.
86
What is the difference between nucleoside and non-nucleoside polymerase inhibitors?
Nucleoside analogues are incorporated into viral RNA/DNA and terminate replication. Non-nucleoside inhibitors bind to allosteric sites to inhibit polymerase activity.
87
How does the immune response contribute to antiviral therapy effectiveness?
A strong immune response can clear residual virus after drug-induced suppression, while immune evasion can undermine therapy.
88
Why is drug half-life important in antiviral therapy?
A longer half-life allows less frequent dosing, improves compliance, and maintains therapeutic levels to suppress viral replication.
89
What is 'viral fitness' and how does it relate to resistance mutations?
Viral fitness refers to the ability of a virus to replicate and transmit. Resistance mutations can reduce fitness, but compensatory mutations may restore it.
90
What is a pharmacophore model in drug design?
It’s a theoretical model that defines the essential features of a molecule required for its biological activity, guiding compound design.
91
How can computational docking aid antiviral drug discovery?
Docking simulates how a drug binds to its target, predicting affinity and helping screen large compound libraries virtually.
92
What are the ethical challenges in early antiviral drug testing?
These include exposing humans or animals to potentially toxic compounds and testing in vulnerable populations during outbreaks.
