Nucleic Acids Flashcards
What are nucleic acids composed off
4 or heterocyclic bases
what are the 2 pyrimidne bases
cytosine thymine
what are the 2 purine bases
adenine guanine
what do heterocylic base attach to form a nucleoside
5 memebered sugar unit
at what positions do phosphate linkages form
3’ and 5’
what is the uncommon base
uracil and it is a replacement for thymine
describe an A - Dna helix
RNA RNA and RNA DNA Helix with a short wide shape
deep narrow major grove with a wide shallow minor groove
base pair tilted to helix axis
c3’ endo
describe a B - DNA helix
DNA DNA with a narrow longer helix
Wide major groove
Narrow minor groove
base pair perpedicular to helix axis
c2’ endo
describe a Z - DNA helix
left handed
narrow long helix
narrow deep minor group
alternating anti syn conformation
what are the different ways a drug molecule can interact
intercalating agents
topoisomerism poisons
alkylating agents
chain cutters
chain terminators
describe how a DNA forms a protein
DNA replicates Transcription RNA Translation Protein
what are intercalating agnets
contain planar or heteroaromatic structures which fit between the DNA base pairs
what are intercalating agents held in place by
van der waals interactions
what is doxorubicin
highly effective anti cancer drug
what does doxorubicin do
intercalates with DNA
how does doxuribicin intercalate with DNA
approaches from the minor groove and intercalates using the planar tricyclic structure
what does doxorubicin do
hinders the normal action of topoisomerase II, an enzyme involved in replication.
what is doxorubicin referred to
inhibit the enzyme so is referred to as a poison
what is super coiling
dna must be coiled int oa more compact structure to fit into the nucleus
what does super coiling require
super coiling requries one stretch of DNA to cross over another and this process is catalysed by topoisomerase enzymes
what is doxorubicins effect on super coiling
stablises the enzyme DNA complex and hinders the process
what do non intercolating poisons do
fluroquinolones can interact with the DNA enzyme complex and inhibit biological function
The binding site for the drug appears only after DNA has been cleaved by the topoisomerase enzyme.
Planar core will stack through Van der Waals interactions, substituents at C6 and C7 positions can bind to the enzyme.
Carbonyl oxygen can form H-bonds with DNA.
what is an alkylating agent
highly electrophilic molecule which will react with necleophilic groups within the heterocyclic DNA bases
what can alkylating agents form
inter or intra strand crosslink
what do interstand crosslinks do
disrupt replication and transcription by hindering separation of strands
what do intrastrand crosslinks do
mask DNA structure from enzymes involved in replication and transcription
what are the downside of alkylating agents
lack selectivity
how do alkylating agents act as anti cancer
they reduce toxicity by formation of the active species during metabolism
what is one of the most widely used anticancer drugs in medicine
cis platin
what happens when cis platin enters the cellular environment
chlroide substituents are dispalaced by water
active species then forms intrastrand crosslinks in regions contraining adjacent guanine bases
attachement of the drug is thought to disturb the hydrogen bonding between the heterocyclic bases resulting in local unwinding of the helix
very lowselectivity for cancer cells causes high toxicity of drug
what are chain cutters
these drugs will cleave DNA and prevent the enzyme DNA ligase from repairing the damage
thought to work through a radical mechanism resulting in oxidative cleavage of the DNA structure
what do chain terminators do
inhibit DNA replication by acting as false substrate
what do chain terminateors lack
functional groups requriered for further chain growth so incorporation into a growing DNA chain will reuslt in termination
what are chain terminators used for
antiviral drugs
treatment of HIV targeting reverse transcriptase
what does stabilisation of the gene helix
stabilisation of the double helix will inhibit the processes involved in transcription and ultimately protein synthesis
what are the two modes of action of antisense therapy
steric block
cleavage by RNaaseH
what are the optimal characteristics of RNA
duplex stability specificity nuclease stability cellular uptake toxicity
what does a too short chain mean
lead to targetting of other regions of RNA
what does a too long chain mean
mismatched sequences
what is the ideal chain length
20-25 bases
what shows the greatest therapeutic potential
requires continueous stretch of DNA bases of 6-10 residues
what does modification require
requires continuous stretch of DNA bases of 6-10 residues containing a phosphodiester or phosphothioate linkage
what form of linkage are more resistant to nuclease degradation
phosphothiaote linkage
what do 2nd generation antisense drugs use
a gapmer principle
2nd generation antisense
Core region of phosphorothioate linkages are flanked by regions containing other modification.
They enhance the stability of DNA:RNA duplex, and therefore modifications that induce the C3’-endo sugar pucker are desired.
Also enhancement of nuclease stability is a consideration.
These modifications can also be used for the steric block approach.
what can small RNA molecules present in the cell be used to control
gene expression and protect against viruses
what are micro RNA
small double stranded RNA molecules are produced from larger RNA sequences by the dicer enzyme
what are micro RNA produced from
larger RNA sequences by the dicer enzyme
describe RNA INTERFERANCE
The miRNA then binds to a complex of enzymes known as RISC (RNA inducing silencing complex).
In the RISC complex one strand is discarded to produce the small interfering RNA sequence (siRNA).
This binds to a complementary mRNA and induces cleavage of the mRNA.
Key points of RNA interference
dsRNA cleaved by Dicer to give miRNA.
Loading into RISC complex gives siRNA.
Recognition of mRNA by active RISC complex.
Cleavage of mRNA results in inhibition of protein synthesis.
Cleavage of viral RNA halts attack.
what do siRNA do
silence target gene
what is antigene therapy
similar to antisense approach but targets the DNa double helix rather than the RNA
Conventional drugs that target DNA have low selectivity for the target sequence
targeting of the DNA base pair will provide increased specificity
