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Frontiers in infectious diseases > 14. Antiviral drug discovery > Flashcards

14. Antiviral drug discovery Flashcards

1
Q

What are antiviral drugs?

A
  1. Medications designed to inhibit viral replication
  2. They are specific stages of the viral life cycle like entry, genome replication and viral release.
  3. Antiviral drugs do not destroy viruses directly but rather interfere with their ability to replicate and spread.
  4. Some antivirals are broad spectrum and other are highly specific
  5. We have good antivirals that can target a limited range of viruses
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2
Q

When was the first antiviral approved?

A

1961

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3
Q

What has sped up antiviral drug development?

A

The COVID pandemic

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4
Q

How many viruses can be treated with antivirals?

A

Less then 10

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5
Q

What viruses can be treated with antivirals?

A
  1. HIV
  2. Hepatitis C
  3. Hepatitis B
  4. Herpesvirus
  5. Influenza
  6. Papillomavirus
  7. SARS-CoV-2
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6
Q

Which virus has the most treatments available?

A

HIV

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7
Q

Why do we need multiple drugs for the same target in the same virus?

A
  1. This is due to the high mutation rate of viruses.
  2. This especially applies to RNA viruses.
  3. Most antiviral treatment uses more than 1 drug at a time to prevent development of resistance.
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8
Q

What stages in the virus lifecycle do antivirals target?

A
  1. Viral attachment and fusion
  2. Prevent genome replication by inhibiting RNA/DNA replication
  3. Block reverse transcriptase in retroviruses.
  4. Prevent viral proteins maturation like cleavage of polyproteins
  5. Prevent viral DNA integration into the host genome.
  6. Prevent viral release
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9
Q

What classes of antiviral drugs are there?

A
  1. Entry inhibitors.
  2. Polymerase inhibitors.
  3. Reverse transcriptase inhibitors.
  4. Protease inhibitors
  5. Integrase inhibitors.
  6. Neuraminidase inhibitors.
  7. Immunomodulators.
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10
Q

How are immunomodulators used to treat viruses?

A
  1. They enhance the host immune response against the virus.
  2. They are often a 1st line approach when you don’t know a diagnosis.
  3. These prompt a stronger immune response to the virus.
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11
Q

What is the most desirable antiviral?

A

One that selectively targets the pathogen without harming the host.
“magic bullet”

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12
Q

What viruses had treatments developed first?

A
  1. Viruses that were the most problematic on human health.
  2. eg smallpox or HIV
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13
Q

What virus had the 1st large scale screening efforts to find antivirals?

A
  1. Smallpox
  2. This stopped once the vaccine was developed.
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14
Q

What was the 1st antiviral?

A
  1. Idoxuridine
  2. Approved in 1962.
  3. Used to treat Herpes Simplex Keratitis
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15
Q

Why did antiviral drugs discovery speed up in the 60s and 70s?

A
  1. Due to the success of antibiotics.
  2. We had improved understanding of viral replication
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16
Q

How did blind screening contribute to antiviral drug discovery?

A
  1. Random screening of chemical and natural products.
  2. They were tested for their ability to inhibit viral replication in cell culture.
  3. “Hits” were further purified and tested for safety and efficacy in animal models.
  4. “Leads” are refined using medicinal chemistry to reduce toxicity, increase solubility and bioavailability.
  5. The mechanism of action for these drugs is often unknown.
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17
Q

What is the path of drug discovery?

A
  1. It is a very complex path that drugs can fail at anytime.
  2. It is very expensive to take a drugs from hit to approval (around £1 billion).
  3. Start with in vitro cell cultures
  4. Then move onto in vivo animal models. You need find a suitable model.
  5. Then preclinical development
  6. Then clinical trials which is very expensive and normally requires a pharmaceutical company due to cost. There are 3 main phases with increasing participants and barriers to approval.
  7. Drugs undergo further review even once the drug is licensed.
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18
Q

How can targets for antiviral drugs be identified?

A
  1. Affinity based approaches
  2. Phenotype based approaches
  3. Genetic based approaches
  4. Computational based approaches
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19
Q

Antiviral target identification: Affinity based approaches

A

This looks at the direct binding of the candidate to the viral proteins.

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20
Q

Antiviral target identification: Phenotypic based approaches

A

This looks at what happens to the cell phenotype if the targeted protein is modulated.

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21
Q

Antiviral target identification: Genetic based approaches

A

This looks at what happens if you knock out in induce expression of the target protein what happens.

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22
Q

Antiviral target identification: Computational based approaches

A
  1. This uses data to model what could happen if the protein is targeted.
  2. Problem is if the data is not good enough you won’t get good predictions.
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23
Q

How can drug efficacy be determined by screening?

A
  1. Mechanism based screening
  2. Cell based screening
  3. High-throughput screening
  4. All of these use compound libraries
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24
Q

Drug Efficacy Screening: mechanism based screening

A
  1. The target is identified and this leads to assay development.
  2. These target are enzymes, ion channels and receptors.
  3. This is more rigorous then cell based screening as you can see the isolated effect of the compound on the activity of the specific target.
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25
Q

Drug Efficacy Screening: cell based screening

A

Essential elements of the virus function to be disrupted are engineered into a cell in combination with a reporter system.

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26
Q

Drug Efficacy Screening: High-throughput screening

A
  1. Mechanism or cell-based screens that are done in an automated fashion.
  2. Done in a small volume multiwell format to screen thousands or millions of compounds a day.
  3. Use compound libraries
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27
Q

What is mechanism based screening using HIV as an example?

A
  1. You have a hypothesis of what the drug is effecting like a HIV protease.
  2. Then isolate the drug and the protein together.
  3. Observe the effect of the drug on the protein by running on a gel.
  4. To make this high throughput use fluorescence and automated detection.
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28
Q

What can automated high-throughput screening do?

A
  1. They can plate and culture cells.
  2. They can plate the antiviral candidates.
  3. They can also do the initial data interpretation.
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29
Q

What methods are used for rational drug design?

A
  1. Structural based design
  2. in silico drug discovery
30
Q

What is structure based design?

A
  1. A rational drug design method.
  2. It requires that atomic structure of the target molecules and understanding of the mechanisms of action of the target.
  3. Structure can be determined by X-ray crystallography, NMR or CryoEM.
  4. Gives insight into ligand design against specific targets.
  5. It is possible to design and optimised a compound that binds specifically to the active site of the target and inhibit its activity.
31
Q

What is rational drug design?

A
  1. Previous methods are based on chance.
  2. They are also limited by compound libraries.
  3. Rational drug design creates a compound that is specific for the target.
32
Q

What is in silico drug discovery?

A
  1. Systematic testing of compounds and their known interactions with targets by virtual screening and iterative docking.
  2. An average supercomputer can screen 200 million compounds against 5000 proteins in a number of months.
  3. Screening molecules against the target by knowing the structure of both.
33
Q

What is HIV and what treatments are available?

A
  1. HIV causes chronic infection and progressive immune deterioration lead to AIDS.
  2. The 1st antiretroviral drug AZT was approved in 1987, marking the beginning of HIV treatment but it didn’t cause a big change right away.
  3. Combined antiretroviral therapy (cART) emerged in the mid-1990s dramatically improving survival of people living with HIV.
  4. ART doesn’t cure the infection but it reduces viral load and prevents immune system deterioration.
  5. ART has transformed HIV from a fatal disease to a manageable chronic condition.
34
Q

What steps in the HIV lifecycle can be treated with antiretroviral drugs?

A
  1. Almost every step of HIV replication.
  2. Entry
  3. Nuclear import
  4. Reverse transcription
  5. Integration
  6. Transcription
  7. Translation
  8. Assembly and maturation
35
Q

Why is combination therapy required to treat HIV?

A
  1. Monotherapy and 2 drug therapy only causes a short drop in viral load.
  2. Only combination therapy can stabilise the viral load at very low levels.
  3. This is due to the mutation rate of the virus and development of resistance
36
Q

Why could a HIV capsid inhibitor transform HIV treatment?

A
  1. It can be given every few months as an injection instead of daily.
  2. This can simplify and advance HIV treatment.
37
Q

How can ART be used as prophylaxis?

A
  1. This is not a vaccine but gives a window of opportunity to prevent infection.
  2. Still uses antiviral but has a limited time window.
  3. Pre-exposure prophylaxis is a daily mediation for HIV prevention.
  4. Post-exposure prophylaxis is an emergency treatment taken within 72 hours of exposure.
38
Q

What is Hepatitis C virus and what treatments are available?

A
  1. HCV causes chronic liver infection, leading to cirrhosis, liver failure and cancer.
  2. Initially HCV was treated with interferon (immune modulator) and ribavirin which had low cure rates, severe side effects and long treatment duration.
  3. In 2010s direct acting antivirals (DAAs) revolutionised HCV treatment by directly targeting viral proteins.
  4. Modern DAAs achieve cure rates of over 95% in around 8-12 weeks with few side effects
  5. DAAs have made HCV eradication a realistic goal
39
Q

What are the main targets of direct acting antivirals (DAAs)?

A
  1. They only work if you target multiple targets to prevent resistance.
  2. Inhibit the NS3 protease helicase to prevent polyprotein cleavage.
  3. Inhibit NS5A to prevent membranous web formation and replication.
  4. Inhibits NS5b which is the RNA-dependent RNA polymerase.
40
Q

What model system was used for DAA development?

A

Subgenomic replicon RNAs

41
Q

What are subgenomic replicon RNAs?

A
  1. A method of culturing viruses in cells that is used to test potential antivirals.
  2. Subgenomic replicon RNAs are transcribed in vitro and introduced into cells.
  3. Only cells where the replicon self-amplifies survive neomycin selection.
  4. This forms stable HCV replicon cell clones.
42
Q

What is Hepatitis B virus and what treatments are available?

A
  1. HBV causes chronic liver infection, leading to cirrhosis, liver failure and hepatocellular carcinoma.
  2. Totally different virus to HCV that leads to a similar disease.
  3. Interferon-alpha was the 1st approved therapy but has low success rates and significant side effect. It is still often used.
  4. Nucleoside analogues (NAs) like tenofovir suppress HBV replication by inhibiting reverse transcription but don’t cure the infection
43
Q

What current treatments are being developed for HBV?

A
  1. RNAi
  2. CRISPR-cas based therapies.
  3. Immune modulators.
44
Q

Why is there overlap between HBV and HIV treatment?

A
  1. Both viruses are retroviruses so similar treatments can be used.
  2. This is a broad spectrum treatment.
  3. This simplifies treatment as drug repurposing is cheap and easy.
  4. Also HBV and HIV are often transmitted as dual infections due to similar transmission routes.
45
Q

What is influenza virus and what are the treatment available?

A
  1. Influenza virus is a highly contagious RNA virus causing seasonal flu outbreaks and pandemics.
  2. Antiviral work best when taken within 48 hours of symptom onset.
  3. There are 3 main classes of antivirals for influenza: Neuraminidase inhibitors, Cap-dependent endonuclease inhibitors, M2 ion channel inhibitors.
  4. The most common treatment is neuraminidase inhibitors.
46
Q

How do neuraminidase inhibitors work?

A
  1. They are designed to interact with conserved amino acids essential for neuraminidase function.
  2. This blocks the release of the virus.
  3. This is a selective treatment so increases chance of effective therapy.
  4. It has broad anti-flu activity with few side effects.
  5. They have a limited window of treatment.
  6. Mutations that cause resistance should be rare as they could compromise enzyme activity and fitness.
  7. Eg Tamiflu
47
Q

What is SARS-CoV-2 and what treatments are available?

A
  1. SARS-CoV-2 is a positive sense ssRNA virus from the Coronaviridae family.
  2. Responsible for COVID-19 pandemic.
  3. There are 3 main treatments: Remdesivir, Molnupiravir, and Nirmatrelvir/ritonavir.
48
Q

What are Cap-dependent endonuclease inhibitors?

A

They inhibit viral mRNA synthesis to stop replication.

49
Q

What do M2 inhibitors prevent?

A

They prevent viral uncoating

50
Q

What is remdesivir?

A

A nucleoside analogue inhibitor which competes with natural nucleotides for incorporation into viral RNA by SARA-CoV-2 RNA-dependent RNA polymerase.

51
Q

What is Molnupiravir?

A

A ribonucleoside analogue that gets incorporated into the viral RNA during replication inducing catastrophic mutations in the viral genome.

52
Q

What is Nirmetrelvir/Ritonavir?

A
  1. Nirmatrelvir inhibits the viral 3CL protease.
  2. Ritonavir originally developed for HIV is given as a pharmacokinetic enhancer to increase the plasma concentration of nirmatrelvir.
53
Q

What are the 2 main steps targeted to treat SARS-CoV-2?

A
  1. Inhibiting replication by inhibiting the RNA-dependent RNA polymerase.
  2. Inhibiting the main viral protease.
54
Q

What are broad-spectrum antivirals?

A
  1. Most antivirals are very narrow in their activity.
  2. In some cases you want broad spectrum treatment.
  3. These target the same mechanism in different viruses.
  4. They can also target the host mechanisms manipulated by the virus.
55
Q

What is Ribavirin?

A
  1. A mimic of both adenosine and guanine ribonucleosides.
  2. It is the only broad spectrum drug in clinical used that active against RNA viruses.
  3. It is used to treat HCV.
  4. This and interferon are the best treatment options when you have an unknown RNA viral infection.
56
Q

What are the pros of broad spectrum antiviral that target the host?

A
  1. There is a high barrier to resistance as host mechanisms are a lot slower to develop resistance then viral mechanisms.
  2. They have broad genotype/serotype coverage.
  3. Large number of druggable targets.
  4. There is a fast development path for known inhibitors.
57
Q

What are the cons of broad spectrum antiviral that target the host?

A
  1. Potential for more on target toxicity as you are inhibiting part of normal cell functions.
  2. Often poor translation from in vitro to in vivo.
  3. Host polymorphisms can alter the function of the drug.
  4. the mechanisms of action is complex.
58
Q

What are the predictors of antiviral treatment success?

A
  1. Timing of treatment.
  2. Type of viral infection.
  3. For acute infection quick treatment is really important and late treatment can actually be damaging to the patient.
  4. You have longer to interfere with chronic treatment.
  5. Virus that integrate into the genome can be treated for a long time but you can never get rid of them.
59
Q

What are the challenges of antiviral treatment?

A
  1. Drug resistance
  2. Drug delivery
  3. Toxicity and side effects
  4. Limited treatment window.
60
Q

Challenges of antiviral treatment: drug resistance

A

Viruses with high mutations rates can rapidly develop resistance to monotherapies making combination treatments essential.

61
Q

Challenges of antiviral treatment: Drug delivery

A
  1. Some antivirals have poor bioavailability or require specific administration routes.
  2. The treatment needs to get to the right place in the body.
62
Q

Challenges of antiviral treatment: Toxicity and side effects.

A
  1. This is important especially for drugs targeting host pathways.
  2. Toxicity can increase as the dose increases.
63
Q

Challenges of antiviral treatment: Limited treatment window

A

Many antivirals require early administration to be effective.

64
Q

What are the types of drug resistance to antivirals?

A
  1. Treatment-emergent resistance which is the selection of resistance from a wild type infection.
  2. Acquired resistance which is infection with an already resistant strains. These infections are especially a problems for people with chronic infections.
65
Q

How much is HIV treatment developing resistance?

A

In some places 1 in 5 HIV infections are resistant to typically used drugs.

66
Q

What are some new approaches to antiviral drug development?

A
  1. Monoclonal antibodies
  2. AI-driven drug discovery
  3. Personalised medicine
67
Q

New approaches to antiviral drug discovery: monoclonal antibodies

A
  1. Engineered antibodies that can provide highly specific neutralisation of viruses.
  2. They offer immediate therapeutic options particularly for emerging or resistant viruses.
  3. Antibodies could also be harvested from patients and given as passive immunity.
68
Q

New approaches to antiviral drug discovery: AI-driven drug discovery

A
  1. Machine learning and deep learning algorithms may reduce the time and cost of antiviral development.
  2. There are no clear successes from this yet as the current training data is not good enough.
69
Q

New approaches to antiviral drug discovery: personalised medicine

A
  1. Tailored antiviral therapies based on individual immune response or genetic susceptibility and viral strain variations.
  2. Individual therapy is something AI can help with to analyse all the information.
70
Q

How have monoclonal antibodies been used to treat ebola?

A
  1. Cocktails of monoclonal antibodies from vaccinated patients.
  2. These can be used to treat and improve survival after Ebola infection.
71
Q

What is the 1st AI designed antiviral for?

72
Q

Preclinical development of Ritonavir and cobicistat for SARS-CoV-2 treatment

A
  1. Ritonavir and cobicistat are used as a booster to improve HIV treatment.
  2. Initial in silico screening showed cobicistat could inhibit the main SARS-CoV-2 protease.
  3. In vitro cell based screens showed cobicistat reduced SARS-CoV-2 levels in a dose dependent matter.
  4. But the mechanism based screen doesn’t work as biology is messy and the binding wasn’t stable.
  5. However it could inhibit covid in another way.
  6. Cobicistat was actually binding to the spike protein that is essential for fusion and entry of the virus.
  7. In vivo testing in hamsters shows it worked in monotherapy and combination therapy.
  8. It is also effective against other covid variants.
  9. It also worked against MERS.
  10. The take home is research is not simple and you can’t base experiments on what you hope to see.

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