module 5 Flashcards
what are most infectious diseases caused by in North America
viruses (more than 95% of all resp. disease)
all class 4 pathogens are viruses
describe class 1 pathogens
- no risk or limited risk - P1 LAB
- work on open lab bench
- example: e. coli
describe class 2 pathogens
- moderate risk - P2 LAB
- limited access to lab, lab coat required
- laminar hoods used (unidirectional air flow)
- example: herpes
describe class 3 pathogens
- restricted access, special training required - P3 LAB
- surgical gowns. gloves, respirators
- all air and liquids coming in or out are treated or filtered
- everything coming out is autoclaved and incinerated
- example: HIV, Y. Pestis
describe class 4 pathogens
- lethal, highly infectious and untreatable - P4 LAB
- lab accessed by airlock, special training
- space suit, shower
- low pressure in lab, airlocks
- all liquids and gasses filtered going in or out
- example: Ebola, smallpox, Marburg
describe the general structure of viruses
- protein capsid surrounds genetic information
- some capsids can also carry viral proteins and enzyme
- some viruses are enveloped which means capsids surrounded by a membrane containing viral proteins
what are 2 elements common to all viruses
- duplication of genetic info
- production of viral protein
what are oncogenes
- cancer causing mutated gene
- structurally related to host proteins
how do viral proteins work
- viral protein bind to post protein and alter it’s protein function
- control cellular regulatory systems
- utilize host proteins and machinery (ribosome + nucleic acid polymerase)
what do ribosomes do
protein formation
what do nucleic acid polymerase do
nucleic acid formation
what are 3 antiviral drugs that exist today
- hepatitis C (cure)
- herpes (treat)
- HIV (manage)
what is the all time greatest achievement in medicine
- immunization (biologics)
- small pox: eliminated
- polio (almost eliminated)
- measles
- mumps
where are most viral enzymes involved
nucleic acid replication
list steps of the viral life cycle
What are major problems with antiviral drugs
- selectivity
- diagnosis
- resistance
what are the difficulties in developing antiviral drugs
- each virus is unique
- most viral proteins act by binding to host proteins
drug target for adsorption and penetration (step 1)
- UNLIKELY DRUG TARGET
- limited success in HIV
- maraviroc as a small molecule which prevents unwinding of viral cell
drug target for release of viral nucleic acid (step 2)
- UNLIKELY DRUG TARGET
- 2 successful drugs
- influenza and block ion channel
drug target for synthesis of regulatory proteins (step 3)
- UNLIKELY
- NO DRUGS EXIST FOR THIS PHASE
drug target for synthesis of nucleic acid (step 4)
- MOST DRUG TARGET
- require unique viral enzyme (RNA polymerase)
drug target for synthesis of structural proteins (step 5)
- UNLIKELY
- protease drugs for HIV and Hepatitis C
drug target for assembly (step 6)
- UNLIKELY TARGET
drug target for release (step 7)
- UNLIKELY TARGET
- few drugs (HIV and Influenza)
what makes some viral cycle steps bad targets
- protein protein interactions
- proteins bind tightly and use large contact surfaces
- difficult to target as drugs are small molecules
describe the requirements of viral enzyme targets
- structurally unrelated to host enzyme to provide selectivity
describe herpes
- virus causes chronic recurrent infections
- able to escape immense system (latency in neurons
- 2 types: HSV1 and HSV2
Describe HSV 1
- cold sores and blisters on mouth, nose, sometimes eye
- 80% of pop infected
- only 10-20% experience breakouts
- escapes immune system through latency
- trigger by stress and sunlight
- travels down axion to skin cells
Describe HSV1 outbreaks
- lytic infection: only in epithelial cells does not damage neurons
- viral activity short (less than 24 hours)
- viral damage is minimal
- most damage is caused by immune system (over stimulated and destroys most tissue)
- drug needs to be administered quick
Describe HSV 2
- sores and blisters on anus and genitals
- injects 15-20% of population
- infection much more painful than HSV1
- one outbreak per year
- MOST COMMON STD
Describe HSV2 outbreaks
- short viral activity + minimal dmaage
- most damage done by immune system
- drug needs to be administered quick
describe herpes virus structure
- genetic info is DS DNA
- very complex (more than 70 genes compared to usually less than 1)
- has its own polymerase which is drug target
what are the 3 components of nucleic acid
- nucleosides (with phosphate: nucleotides)
- sugar (2 deoxyribose DNA, ribose RNA)
- base (nitrogen containing aromatic hetereocycle)
what are the 4 nucleic acid bases
PURINE
adenosine and guanosine
PYRAMIDINE
- cytidine and thymidine (uracil in RNA)
How are bases recognized
- shape and h bonding pattern
what are the advantages of nucleic acid forming double strands
- stabilizes molecule + long term info storage
- second strand provides an easy way to replicate or read info
- error checking
what is the function of polymerases
- copy nucleic acids
- use one strand as template to make other strand
- nucleotides added one at a time, matching each base against compliment on other strand (AT, GC)
- 3’ OH USED AS NUCLEOPHILE
What is the method used to design drugs to target polymerase
- rational drug design
- use knowledge of enzyme mechanism and substrates
what can poor selectivity lead to
- toxicity, interference with normal cells can lead to problems as they store genes and synthesize protein
what is the selectivity problem with nucleic acids
- must block viral enzyme without blocking host enzyme
what are 2 strategies of targeting polymerase
- non natural base
- chain termination
describe non natural base
- replace base with non natural
- resulting nucleic acid not readable by host enzymes (spelling mistake)
- substrate structure disrupted, polymerase cannot function
what are the requirements for a non natural base
- drug is a substrate for kinase
- drug is a substrate for VIRAL polymerase (into viral nucleic acid and creates unreadable strand)
- DO NOT WANT DRUG TO BE SUSBSTRATE FOR HOST POLYMERASE
EXAMPLE OF NON NATURAL BASE
- idoxuridine
- substrate for both viral and host polymerase so highly toxic due to non selectivity
- topical use only (eye infection of herpes)
describe chain termination
- add something non nucleophilic
- non nucleophilic OH isotere, nucleic acid replication stops
- can be combined with non natural base
what are the requirements for chain termination
- drug is phosphorylated via kinase, viral or host
- drug is a substrate for VIRAL protein
- gets incorporated into viral nucleic acid, stops replication to form short piece of nucleic acid, viral proteins do not get made
- DRUG SHOULD NOT BE SUBSTRATE FOR HOST POLYMERASE
Explain chain terminator toxicity
- drugs have structures similar to normal substrate
- drugs incorporated into host nucleic acid by host polymerase
- improve selectivity by changing the sugar
describe acyclovir
- very high selectivity for virally infected cells
- selectivity due to bioavailability
- low incidence of side effects
- low severity of side effects
- is a prodrug, only phosphorylated in viral kinase
- selectivity caused by THYMIDINE KINASE
- FOUND BY GERTRUDE IN 1974
describe how acyclovir is a clean drug
- circulates randomly in body
- accumulates only in virally infected cells
- drug concentration in normal cells too low to cause problems (diffuse in and out)
