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Antimicrobials 2 - Antivirals Flashcards

1
Q

Fungi: what do they include, feed on, reproduction, pharma relevance?

A
  • mold, mushrooms, yeast
  • feed on decomposing organic matter
  • reproduce sexually and asexually through spores
  • source of antibiotics (ex. penecillins) and other drugs
  • can symbiotic (lichen) or pathogenic (candidias)
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2
Q

What kind of cells are fungal cells? What are they similar to? What is in their cell wall?

A
  • eukaryotic (have nucleus)
  • similar to plant cells –> membrane, cell walll, nucleus, mitochondira, cytoplasm
  • chitin (instead of cellulose) and glucan and manoproteins –> only organism to have chitin and glucan in cell wall
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3
Q

history of antifungals

A
  • pre 1990s - home remeides of vinegar and gynpowder
  • early 1990s - general antiseptic gentian violet that binds to thioredoxin (protein in redox cycle of fungi that results in death if malfunctions)
  • first true antifungal: Amphotericin B (polyene) from soil bacteria in 1955
  • flucytosines (1970), azoles (1990), echinocanids (2000)
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4
Q

What do antifungals target?

A
  1. cell wall/membranr
  2. fungal DNA
  3. protein synthesis
  4. essential cellular processes
  5. virulence factors
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5
Q

How do fungi acquire resistance? And how is this different from bacteria?

A
  1. block drug entry
  2. pump it out
  3. metabolize it
  4. mutate drug target
  5. avoid the pathway

but there is no transformation or conjugation because they dont have a mechanism for DNA transfer –> resistance grows slower than in bac

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6
Q

What are the 5 antifungals?

A
  • amphotericin B
  • nystatin
  • fluconazole
  • griseolfulvin
  • flucysteine
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7
Q

Amphotericin B

A

What is it?
- Naturally occuring antifungal

Use
- blastomyces respiratory disease
- serious infections only

MOA
- binds directly to ergosterol in fungal cell wall and causes permeability –> leakage
- fungocidal

PK
- not orally bioavailable but is okay in the gut
- administered IV or lipid formulation

ADR
- toxi effects are dose dependent
- low TI (can bind cholesterol)
- hypotension
- anorexia
- kidney/liver damage

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8
Q

Nystatin

A

What is it?
- polyene antifungal made from streptomyces bacteria

Treatment
- candida, oral thrush
- broad spectrum

MOA
- directly binds to ergosterol (fungal specific sterol) in cell membrane and causes permeability by forming TM pore–> leakage
- fungicidal

PK
- not orally bioavailable (large polyene striucture)
- administered topically or for GI –> not absorbed

  • good safety profile
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9
Q

fluconazole

A

What is it?
- synthetic azole antifungal - has azole rings

Treatment?
- oral trush and yeast infection
- broad spectrum

MOA?
- blocks ergosterol fluidity by blocking 14-demethylase (CYP450) that catalyzes lanosterol into ergosterol
- causes permeability and leakage
- fungicidal

PK?
- water soluble and very bioavailable
- administered orally and IV

ADR? Safety?
- very safe because we use HMG-CoA reductase –> selective
- minor GI issues

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10
Q

griseolfulvin

A

What is it?
- naturally produced antifungal

Treatment?
- nail and systemic infection

MOA?
- directly binds to tublin and leads to impaired microtubules –> blocks mitosis/replication
- fungistatic

PK?
- orally admin for superficial infections

ADR? Safety?
- sunlight sensitivity, yellowing of skin, liver damage, links to cancer –> can be used to treat cancer?
- slightly more selective for fungal tubulin but can also induce mutations in humans

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11
Q

flucytosine

A

What is it?
- synthetic base analogue

Treatment?
- systemic infections
- combination therapy for serious infections

MOA?
- prodrug converted by cytidine deaminase to 5-fluorouracil –> converted to NTP –> blocks DNA/RNA synthesis
- fungistatic

PK?
- orally bioavailable

ADR? Safety?
- blood count
- liver/kidney damage
- not safe in pregnancy
- possible carcigonen –> 5FU is toxic to human cells (used in chemo)

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12
Q

Side effects and contraindications of antifungals

A
  1. toxicity and DNA damage
    - DNA damage from nucleotide analogues that can be incorporated into DNA of human cells (FLYCYTOSINE, GRISEOFULVIN)
    - liver and kidney toxicity (AMPHOTERICIN B)
  2. allergic reaction
    - mild to serious
    - specific to drug
  3. GI issues - from nausea to diarrhea
  4. Pregnancy
    - FLUCYTOSINE AND GRISEOFULVIN NOT OKAY
    - FLUCONAZOLE was thought to be okay but new evidence suggests increased risk of miscarriage
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13
Q

What is a virus? What is its replication cycle? What genomes they that have?

A
  • small particle containing RNA or DNA and capsid and sometimes envelops proteins
  • not alive and reliant on host cell for replication and metabolism

replication cycle
attachement –> prenetration –> uncoating –> replication –> assembly –> release (lytic vs lysogenic)

genomes
- ssRNA, ssDNA, dsDNA

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14
Q

how do viruses interact with the host genome

A
  1. transiently - non permanent and non intergarting
  2. permanent but not integrating: episome - an extra chromosome piece that replicates independently
  3. permanently
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15
Q

how are viruses classified

A
  • genetic component (DNA/RNA)
    -morphology
  • mode of replication
  • host: tropism - narrow means they can only go into one or two tissues, broad means they can go into many
  • disease they cause
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16
Q

How do RNA viruses interact with the host genome?

A
  • ssRNA and are non integrating ex SARS Cov 2
  • retrovirus that uses reverse transcriptase to integrate into the host DNA ex. HIV 1
  • dsRNA ex Reovirus
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17
Q

how does RT integrate into the genome?

A
  • makes ssDNA from RNA
  • degardes RNA strand and copies the DNA to form dsDNA
  • goes into the nucleus and integrase helps with integration
  • uses LTR to input DNA into host genome
18
Q

Which viruses are DNA based? How are they categorized?

A

dsDNA: bacteriophage, adenovirus, HSV1/2
- dsDNA viruses can be non-permanent or permanent on episomes (ex. HSC1/2 can be latent or lytic)

ssDNA virsues: parovirus
- usually affects children and canines
- more mature immune systems dont get infected by ssDNA viruses

19
Q

targets of antivirals

A
  1. membrane/envelope - prevent entry and fusion
  2. viral DNA/RNA - polymerase or RT
  3. proteases
  4. glycoenzymes
  5. increase the defences of human cells
20
Q

What are the 5 antivirals?

A

docosanol
acyclovir
zivovudine
nirmatrelvir
amantidine

21
Q

Docosanol

A

What is it?
- emulsifying agent (thickening) - very long lipid with alcohol group

Treatment?
HSV1 cold sore

MOA?
- inhibits the fusion of the viral envelope to the human membrane by directly inserting into the membranr and altering it in a way that blocks fusion
- no resistance!! –> new paradigm –> protecting YOU

PK?
- not orally bioavailable or systemic use
- only for topical infections HSV1 cold sore

ADR?
- low topical absorption
- very safe

22
Q

acyclovir

A

What is it?
- synthetic purine analogue

Treatment?
- HSV1/2, varicella, EBV/CMV

MOA?
- thymidine kinase in virus converts prodrug to monophospahte –> tripphospahte NTP by host kinase –> integrates into DNA and causes chain termination
- our cells don’t have thymidine kinase so we are safe –> selective

PK?
- topical
- oral (prodrug increases absorption)
- IV
- good distribution

ADR?
- safe unless activated in non infected cells

23
Q

zidovudine

A

What is it?
- thymidine nucleoside analogue

Treatment?
- against retroviruses, HIV

MOA?
- prodrug converted to triphosphate by thymidine kinase –> inhibits reverse transcriptase by competing with natural NTPs –> chain termination –> inabilityt o produce DNA and blocks integration

PK?
- orally bioavaiulable

ADR?
- complications in bone marrow
- act on mitochondrial DNA pol

24
Q

nirmatrelvir

A

What is it?
- peptidomimetic

Treatment?
- covid 19

MOA?
- inhibits 3C like protease of SARS COV 2 –> competitive inhibitor that blocks viral replication (dummy substate for protease)
- (3C like protease is reposible for cleacing large pro-proteins into individual proteins)

PK?
- orally bioavailable

ADR?
- generallt well tolerated
- rebound effect

25
amantidine
What is it? - tricyclic amine Treatment? - influenza A MOA? - blocks M2 ion channels in envelope imporatnt in viral uncoating envelope and insertion of protein into in host membrane for genetic delivery--> blocks replication PK? - orally bioavailable ADR? - CNS effects - teratogenic - resistance due to mutations of M2 channel
26
Antiviral resistance mechanisms
- high mutation rates and are produced in high numbers --> prone to evolution - resistance arises from - mutations in target proteins that block drug action -mutations in membrane envelope proteins
27
side effects and contradindications of antivirals
1. toxicity and DNA damage - nucleotide analogues release and incoroprated into DNA of health human cells, liver toxicity for AZT 2. allergic reactions 3. GI issues 4. pregnancy - most safe, but drug dependent
28
How do traditional vaccines work
- contain attenuated or inactiated virus or a purified recombinant protein - viral peptide fragments are captured and expressed on antigen presenting cells (APCs) - APCs activate T and B cells --> cytotxic T cells and plasma cells --> antibodies and memory cells
29
How do next-generation nucleic acid vaccines work
- contain DNA or mRNA encoding for a specific protein from the virus and transfered into a plasmid - delivered in a safe virus or chemical reagent - when inside the cell DNA --> mRNA --> protein - goal is to directly target APC cells so that the protein is expressed on the surface (don't need phagocytosis anymore)
30
What is SARS COV 2
- severe acute respratory syndrome coronavirus 2 - ssRNA vaccine - uses RNA-dependent RNA-polymerase for replication - has 29 proteins - uses spike protein to bind to ACE2 receptors on surface of cells - lung tissue has a lot of these
31
how do the COVID vaccines work?
- use a lipid nanoparticle to package modified RNA (pseudouridine) which encodes teh spike protein - BioNTech uses RNA/LPX that targets dendritic cells - dendritic cells present the protein to B and T cells
32
resistance to COVID-19 vaccines
- evolutionary pressure --> selection of mutations in the spike protein - if the protein changes by 6-8 AA then teh antibody can't clear it --> resistance
33
Concerns and contraindications with vaccines
1. allergic reaction - rare and to components of vaccine 2. off target immune reaction/autoimmune reaction - antibodies generated form vaccine cross react with targets on human cells 3. infection - only an issue with attenuated or partially inactived vaccines, if immune system compromised it might lead to infection 4. pregnancy - only an issue with attenuated and live vaccines causing risk to fetus
34
What are antibodies?
- match between APC and B cell receptor stimulates proliferation of B cell --> matures into plasma cell --> secretes antibodies - antibody antigen complexes are specific - contain fixed structural region and variable region for targeting antigens
35
How are recombinant antibodies produced?
1. identify antibody from library --> immunize rabits and collect serum (natural diversity)/or perfrom an in vitro phage display/or in silico --> this gives monoclonal antibody 2. scale up production - can be performed using expression systems inclusing mammalian or insect cells, yeast, etc
36
How do monoclonal antibodies function as antivirals and what is their PK?
bind to - host viral receptors to block entry - protein in free virus - viral epitopes expressed on host cell --> stimulates secondary effector cells to activate B/T cells PK - not orally bioavailable (stomach pH and proteases) - must be injected - half life is days to weeks
37
Examples of antiviral monoclonal antibodies
1. palivizumab: binds to virus F protein on RSV envelope to prevent fusion 2. ibalizumab: binds to CD4 T cell receptors on HIV to block entry 3. REGEN-COV: made of 2 mAb and binds to 2 epitopes of the COV spike to block binding to ACE2 Rs, admin subcutaenously after exposure
38
Hurdles and contraindications with antibody therapies (5)
1. difficult to produce and purify: have to use expression systems and purify the cellular contaminants 2. can only administer with injection 3. can only be used as a prophylatic or in early stage of infection 4. immune reaction/allergy 5. pregnancy - can pass pregnancy barrier
39
CRISPR/CAS9 as treatment for HIV
goal: target sequence of viral DNA inside cell and leave it to block replication CAS9 - 20pb programmable guide RNA and cleaves dsDNA - excellent specificity, only cuts in cis HIV: integrated retrovirus Cas9 can - disrupt replication genees (1 guide RNA) - cut out the HIV provirus from host genome (cure) (2 guide RNAS) - edit host cell so they lack the receptor for HIV to bind strategy: delivered using safe virus or lipid nanoparticle
40
CRISPR/Cas13 therapy for COV
COV: ssRNA virus Cas13 - 30bp programmable guide RNA that cleaves ssRNA - trans collateral RNA cleavage after cis cleavage (only in bacteria or viruses) - can use it to cleave viral RNA and block replication --> no collateral cleavage is observed in mammalian cells strategy: Cas13 as protein or NA with RNA into cell using safe virus or lipid nanoparticle
41
Contraindications with CRISPR/Cas antiviral therapies
1. viral escape/evolution stimulation - resistance due to mutations in spacer sequence that blocks Cas from cutting --> viruses that have this can be selected and amplified - cleavage can stimulate this too) 2. delivery - difficult to get system into all virally infected cells 3. immune reactions to Cas if introduced into systemic circualtion 4. human genome editing: off target DNA and RNA cleavage of similar human sequences if the enzyme escaped into human cells

PCL470 (14 decks)

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