Antivirals and viruses pharmacology

What is a virus?

Sub microscopic entity consisting of a single nucleic acid surrounded by a protein coat and capable of replication only within living cells

What can viruses infect?

Bacteria, fungi, Protozoa, plants or animals

What type of parasite are viruses commonly referred as?

Obligate intracellular parasite

What do viruses consist of?

• DNA or RNA genome

• Protein coat/capsid made of protein subunits - capsomers

• Envelope derived from plasma-membrane of host but not always present

• Surface proteins/glycoproteins that bind to receptors of host cells

What is a diagram comparing sizes of cells, bacterial, viral and eukaryotes?

What is a diagram showing virion structure?

What are the main way viruses are classified? (DO NOT LEARN THE TABLE)

DNA based or RNA based, or RNA to DNA viruses

What are DNA based viruses split into?

ssDNA and dsDNA

What are RNA viruses split into?

ssRNA and dsRNA

What are RNA to DNA viruses classified into?

ssRNA - retroviruses - and dsDNA - hepadnaviruses (single stranded RNA and double stranded DNA) 

What is a diagram showing how different DNA, RNA and RNA to DNA viruses act on mRNA?

How does dsDNA viruses work to become MRNA?

Transcribed into mRNA+ sense

How is ssRNA + viruses made into mRNA +sense?

Can be used directly

How can ssRNA- viruses be made into mRNA?

Transcription of - strand

How can dsRNA viruses be made into mRNA+ strand?

Transcription of - strand as if it is DNA

How is ssRNA + retrovirus made into mRNA+?

Reverse transcription into dsDNA intermediate which is then transcribed by the host cell

How is ssDNA virus made into mRNA+ strand?

Synthesis of other strand into dsDNA intermediate, then transcribed into mRNA + sense

What are some examples of DNA viruses?

Herpesviruses family e.g., Herpes simples virus 1 and 2 and Varicella zoster, hepatitisviruses like hepatitis B 

What are some examples of RNA viruses?

Myxoviruses - influenza, rhabdoviruses - rabies, filoviruses - Ebola

How many nucleotides do small viruses hold?

Max 5000 - not enough for all capsids if made

What proteins must viruses use in order to made capsids?

Many copies of 1 or a few proteins so leads to high symmetry 

Why is the use of many copies of 1 or a few proteins advantageous?

Simpler proteins and self assembly can happen

What is the viral geometry based around?

Single helical axis 

What does the helix axis of viruses allow?

Flexibility and evolved alongside other helical structures e.g., DNA

What property does all helical viruses have?

All enveloped unlike phage and plant viruses

How are most helixes formed in viruses?

Single major protein arranged with constant relationship to each other 

What symmetry is found in viruses?

Icosahedral symmetry

What are the 3 types of cubic symmetry that is very energetically favourable?

• Tetrahedral - 12 identical subunits (2:3)

• Octahedral - 24 identical subunits (4:3:2)

• Icosahedral - 60 identical subunits (5:3:2)

What type of symmetry will only lead to isometric particles?

Cubic symmetry 

What diagram shows the lifecycle of a virus in an animal cell?

What diagram shows the structure of a viral protein?

Energetically stable, has pentamer structure, dimer in green and blue forms a windmill like structure

What do non-enveloped viruses do?

Lyse cells

What viruses are included in herpes viruses?

Herpes simplex viruses, varicella zoster, shingles, cytomegalovirus and Epstein-Barr virus

What conditions are caused by herpes simplex virus?

Genital herpes, cold sores 

How is HSV transmitted?

Cutaneous

What are the symptoms of HSV?

Cutaneous - localised e.g., oral, genital. CNS effects 

Where is the latency site for HSV and VSV?

Neurons

How are HSV and VSV diagnosed?

Clinical, PCR, culture/DFA

What is the antiviral of choice in HSV and VSV?

Aciclovir 

Is there a vaccine for HSV, cytomegalovirus and Epstein-Barr virus?

No

How is VSV transmitted?

Respiratory

What are the symptoms of VSV?

Cutaneous - disseminated and localised 

Is there a vaccine for VSV/shingles?

Yes

How is cytomegalovirus transmitted?

Secretions - oral, urogenital

What are the symptoms of cytomegalovirus?

Systemic, ocular, GI, haematopoietic, respiratory 

What is the latency site for cytomegalovirus?

Monocytes, macrophages

How is cytomegalovirus diagnosed?

Serology, PCR, culture/DFA

What is the antiviral of choice in cytomegalovirus?

Ganciclovir 

How is Epstein-Barr virus transmitted?

Oral secretions

What are the clinical syndromes of Epstein-Barr virus/glandular fever?

Systemic lymphoma

Where is the latency site for EBV?

B cells 

How is EBV diagnosed?

Serology, PCR, Culture/DFA

What is the antiviral of choice for EBV?

None

What are the main properties of herpes viruses?

Large, enveloped virus, double-stranded DNA genome of 100-150 proteins, family is herpesviridae 

What is the lytic herpesvirus life cycle?

Nuclear dependence, temporal gene expression, viral thymidine kinase key, direct cell lysis

What is the latent herpesvirus life cycle?

• Main site of infection - productive infection of epithelial cells, infects secondary site by retrograde transport

• Sensory ganglion - no integration, minimal gene expression, prevents immune recognition

• Secondary site of infection/site of latent infection - sensory neuron

• Site of recurrent infection - productive infection of epithelial cells

What is the reactivation stimulus for herpesvirus?

UV light, infections, stress, immunosuppresion

What are the most commonly used antiviral medicines?

Aciclovir, penciclovir, ganciclovir

What are aciclovir, penciclovir and ganciclovir used to treat?

Herpes virus infections - HSV and cytomegalovirus

When is cytomegalovirus usually treated?

Only in immunocompromised patients

What is the MOA of aciclovir?

Activated by viral thymidine kinases to become inhibitors of viral DNA polymerases and block viral DNA synthesis - allows intracellular phosphorylation to monophosphate derivative, converted to triphosphate which is then incorporated into viral DNA and is an irreversible inactivator of DNA polymerase

What is the PK of aciclovir?

Oral bioavailability 15-21%, 20% protein bond, half life 2.5-3 hours, renally excreted, safe in pregnancy

What are the side effects of aciclovir administered IV?

Lethargy, confusion, tremor and reversible renal dysfunction but all not very common

What are the side effect of aciclovir orally?

Nausea, vomiting, rash, headache

What are some common drug interactions with aciclovir?

Cyclosporin increases renal toxicity and aciclovir can decrease renal clearance of other drugs

What drug is a prodrug of aciclovir?

Valaciclovir

What are the properties of penciclovir?

Similar spectrum of antiviral cover, topical cream, oral treatment with prodrug - famciclovir

What are the properties of ganciclovir?

Predominantly used to cytomegalovirus, more toxic than aciclovir, severe interaction with zibovudine

What are the properties of the influenza virus?

Enveloped negative strand RNA, part of orthomyxoviridae

How many types of flu are there?

3 - A, B, C

What flu types are responsible for seasonal flu?

A and B

Where does synthesis of influenza mRNA/genome replication occur?

Nucleus - unusual for an RNA virus

Where do most RNA viruses synthesise usually?

Cytoplasm

What are the influenza A subtypes divided into?

Presence of haemagglutinin and neuraminidase - 18 H subtypes, 11 N subtypes

What is a table comparing flu A, B and C?

• Flu A is most severe - has subtypes and animal reservoirs and pandemic when in humans, shift/drift antigenic changes

• B is still severe, no subtypes, no animal reservoirs, epidemic and drift antigenic changes

• C is least severe, no subtypes or animal reservoirs, sporadic spread in humans, drift antigenic changes

What is a diagram showing influenza A virus structure?

• Hemagglutinin - receptor binding, membrane fusion and neutralising antibody target

• Neuraminidase - removes sialic acid residues, virion release

• Ion channel - H+ dependant, influenza A

What is a diagram showing influenza life cycle?

What is the pathogenesis for influenza?

Direct cell lysis in upper/lower respiratory tracts

What is the role of the immune response for influenza?

Protective rather than pathogenic, induces virus and type-specific immunity, virus mediated suppression

What drugs can be used to reduce symptom duration of flu and as prophylaxis?

Tamiflu and Rilenza

When are tamiflu/rilenza most effective for flu?

Taken within 48 hours of first symptoms and can reduce duration by 1-1.5 days as well as reducing complication risk

What drugs class are Tamiflu and Relenza?

Neuraminidase inhibitors

What is the API of Tamiflu?

Oseltamivir

What is the API of relenza?

Zanamivir

How do neuraminidase inhibitors work?

Prevents virion release and halters viral replication

What is the PK of tamiflu?

100% bioavailability, renally eliminated

What are the ADRs of oseltamivir/tamiflu?

Nausea and vomiting, headache, cough, blocked nose

What is the medicinal form of zanamivir?

Dry powder inhaler - 2x a day for prophylaxis

What is the PK for zanamivir/relenza?

10-20% inhalation, renally eliminated

What are the ADRs of zanamivir/relenza?

Rash

What is the caution of zanamivir/relenza?

Risk of bronchospasm - care taken in COPD/asthma patients

What is the coronavidae subfamily?

Subfamily of around 40 single stranded RNA viruses that have a high ability to recombine, mutate and infect multiple species/cell types

What is the hosts response to the SARs-COV-2 virus?

Hyperactive - excessive inflammatory reaction e.g, cytokine storm

What part of SARS-COV-2 catalyses the synthesis of IL6?

Structural part of the virion - nucleocapsid protein

What interleukin causes the cytokine storm?

IL-6

What are the challenges for Covid-19?

Lung injury and cardiovascular complications, generalised hyperinflammation, multi-organ damage

What steroid has recently been shown to have a decreaing effect on mortality?

Dexamethasone