Anti-Viral Drugs

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  • Created by: LBCW0502
  • Created on: 25-10-19 12:19
Outline features of virus structure and classification (1)
Viruses consist of a nucleic acid core that contains either DNA or RNA. Protein coat (envelope) composed of glycoproteins (important virus antigens). Glycoprotein becomes attached to receptor sites (polypeptide) on host cell
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Outline features of virus structure and classification (2)
Penetration, uncoating, release of virions in host cell depends on structural coat proteins
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Outline features of viral replication and transformation (1)
Attachment, penetration, uncoating and transfer of viral DNA to nucleus. Early transcription into viral mRNA. Early translation of viral mRNA into enzymes for viral DNA synthesis. Synthesis of viral DNA and late transcription of viral mRNA
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Outline features of viral replication and transformation (2)
Late translation of mRNA to viral structural proteins. Assembly of virus particles in nucleus. Budding from nucleus and release of virions
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State the viral diseases - DNA based viruses
HSV1/2, VZV, herpes zoster, human papilomavirus, cancer, poxvirus
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State the viral diseases - Resultant diseases of DNA based viruses
Herpes (skin), encephalitis, chickenpox, shingles, smallpox
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State the viral diseases - RNA based viruses
HIV 1/2, rhinovirus, hepatitis A/B/C, influenza A/B/C
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State the viral diseases - Resultant diseases of RNA based viruses
HIV, AID, respiratory/GI infections, common cold, hepatitis, influenza A, B
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Outline the influenza life cyle
Bind to target cell, endocytosis, fusion, replication of genetic material, protein synthesis, budding, release from cell (lysis)
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What is the function of neuraminidase?
Cleaves off terminal sialic acid to allow the virus to leave the cell once the virus has replicated. SN1 reaction
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Describe features of viral neuraminidase inhibitors (1)
Inhibiting the viral neuraminidase prevents the virus from leaving the cell and infecting others. NA is found in both influenza A and B viruses. NA is a glycoprotein. Viruses are bound to NA through sialic acid (NA cleaves sialic acid moiety)
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Describe features of viral neuraminidase inhibitors (2)
Want design of neuraminidase inhibitor to be similar to transition state (bind to active site of neuraminidase enzyme). DANA (nonselective, change sp3 to sp2 hybridisation, too many optically active centres/chiral centres, needs simplification)
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Describe features of viral neuraminidase inhibitors (3)
Replace OH, guanidine group interacts with receptor. Form Zamanivir Relenza. Simplified structure. Modified to form Oseltamivir Tamiflu (drug optimisation, alcohol, guanine, amine, generate reactive molecule, rationale drug design)
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Describe features of HSV (1)
Cause of several painful skin/eye infections. HSV1 (orofacial, cold-sores on mouth and lips). HSV2 (genital herpes). Dormancy periods (often for several year periods). Infectious (potential greatest during outbreak). Currently incurable (not fatal)
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Describe features of HSV (2)
Prevalence of HSV in US - HSV1 (50 million), HSV2 (40 million)
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Describe the process of DNA synthesis (1)
Joining of nucleotides (double strands), 5' to 3', 3' to 5'. Phosphates removed from nucleoside (base, sugar, phosphate) to form phosphodiester bond with OH group on previous nucleotide
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Describe the process of DNA synthesis (2)
Guanine - base, sugar, nucleotide (needs to become a nucleotide to be used in DNA synthesis)
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Describe features of acyclovir
A drug primarily used to treat herpes infections (HSV 1/2). Thought of as a purine mimic. Similarity to 2'-deoxyguanosine, lack of 3'OH
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Describe the MOA for acyclovir (1)
Host thymidine kinase – puts first phosphate on. In healthy cells – molecule doesn’t work at all. In viral cells – thymidine kinase puts a phosphate on. Drug only works on the infected cells (selectivity). Host monophosphate kinase – add phosphate
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Describe the MOA for acyclovir (2)
Host diphosphate kinase – add phosphate. DNA polymerase can take this into DNA synthesis. Acyclovir triphosphate in DNA synthesis – incorporated into DNA. Another nucleotide cannot be used in DNA synthesis
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Describe the MOA for acyclovir (3)
DNA synthesis terminated (no 3-OH to form phosphodiester bond)
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What is the issue with acyclovir?
PK, fairly poor oral absorption (15-30%)
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How is the bioavailability of acyclovir improved? (1)
Design suitable prodrugs. Valacyclovir (50% oral absorption) – valine amino acid – recognised by valine amino acid transporter pept1 transporter, prodrug
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How is the bioavailability of acyclovir improved? (2)
Desiciclovir, 70% oral absorption (another prodrug) – no carbonyl group, oxidised to form active drug. Ganciclovir. Triphosphate on drug molecule (very negative/hydrophobic, issues with drug penetration, better to use nucleic acid base)
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Describe features of idoxuridine
Also used to treat herpes infections (HSV1/2, VZV). Pyrimidine nucleoside mimic. Similarity with 2-deoxythymidine (iodoiuridine base)
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What is the MOA for idoxuridine?
Inactive, thymidine kinase add phosphates, during DNA synthesis (nucleic acid base with different H bond to ido, leads to production of faulty protein, defective viral particles)
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Describe features of HIV
Infection of CD4+ T cells. 3 main drug targets - HIV reverse transcriptase, HIV integrase, HIV protease. X-ray crystal structures solved for all 3 targets. Co-crystallisation with known inhibitors. Facilitates structure-based drug design
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Describe the MOA for AZT
AZT (base, sugar, azide N3 group instead of OH). Phosphate added via host thymidine kinase, HIV reverse transcriptase, fake nucleotide added to DNA product-viral RNA template complex - chain termination
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Describe features of aspartate proteases (1)
Digestive enzyme pepsin. Some proteases found in lysosomes. Kidney enzyme renin HIV protease. Two aspartate residues participate in acid/base catalysis at active site
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Describe features of aspartate proteases (2)
Initial reaction - on aspartate accepts proton from active site H2O which attacks carbonyl carbon of peptide linkage. Simultaneously, other aspartate donates proton to oxygen of peptide carbonyl group
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Describe features of aspartate proteases (3)
2 aspartic acids, water molecule, peptide bond broken using enzyme (design drug to target enzyme). Aspartate breaks up water molecule to form OH, nucleophile attacks carbonyl, pick up proton to form intermediate, hydrolysis of amide
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Describe features of HIV protease inhibitors
Post-translational cleavage of new HIV peptides. Preparation and processing. Inhibitor design – tetrahedral intermediate (transition state). Rational design of molecule
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Describe the concept of a transition state inhibitor (1)
Designed to mimic transition state of enzymatic reaction. Likely to bind stronger to active site than natural enzyme substrates. Successful transition state inhibitor will be transition state isostere (mimics tetrahedral centre, cannot be hydrolysed)
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Describe the concept of a transition state inhibitor (2)
Transition state is sp3 hybridised. Substrate (OH groups). S1 – keep aromatic ring. S1’ – keep proline. IC50 of 6500 nM (concentration at which there is 50% inhibition). Add S2 (amide group) to drug molecule. IC50 reduced to 140 nM
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Describe the concept of a transition state inhibitor (3)
Optimise drug molecule further to get IC50 of 23 nM
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Give examples of HIV protease inhibitors (1)
Saquinavir - first PI on market, rapid development of resistance, low oral bioavailability, strong plasma protein binding. Ritovir - although larger, better bioavailability, good in combination with other PI, strong plasma protein binding
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Give examples of HIV protease inhibitors (2)
Indinavir - design based on Saquinavir, better oral bioavailability, low plasma protein binding
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What is the HIV combination therapy?
HAART - Highly Active Anti-Retroviral Therapy - consists of indinavir, AZT and lamivudine (virus will not be able to maintain replications due to interferences with the processes)
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Other cards in this set

Card 2

Front

Outline features of virus structure and classification (2)

Back

Penetration, uncoating, release of virions in host cell depends on structural coat proteins

Card 3

Front

Outline features of viral replication and transformation (1)

Back

Preview of the front of card 3

Card 4

Front

Outline features of viral replication and transformation (2)

Back

Preview of the front of card 4

Card 5

Front

State the viral diseases - DNA based viruses

Back

Preview of the front of card 5
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