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PM2A Spring Amy L > Nucleic Acids [Brazier] > Flashcards

Nucleic Acids [Brazier] Flashcards

1
Q

Which 2 nucleic acids are purines?

A

Adenine

Guanine

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2
Q

Which 2 nucleic acids are pyrimidines?

A

Cytosine

Thymine

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3
Q

NAme the 5 nucleic acids

A 
Adenine
Guanine
Cytosine
Thymine
Uracil (instead of thymine in RNA)
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4
Q

What are nucleic acids composed of?

A

Heterocyclic bases

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5
Q

What is a nucleoside?

A

A heterocyclic base (nucleic acid) attached to a 5-membered sugar unit
Deoxyadenosine, Deoxyguanosine, Deoxythymidine, Deoxycytidine

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6
Q

What is the sugar unit in DNA?

A

Deoxyribose

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7
Q

What is the sugar unit in RNA?

A

Ribose

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8
Q

How are the nucleosides connected?

A

By phosphate linkages between the 3’-5’ positions

sugar-phosphate backbone

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9
Q

How do nucleic acids form a double helix

A

Complementary base pairing between 2 strands to form a double helix
A-T, C-G

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10
Q

How do nucleic acids bond?

A

Via hydrogen bonding
A-T form 2 hydrogen bonds
C-G form 3 hydrogen bonds

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11
Q

What is syn-anti conformation?

A

The orientation of the heterocyclic base to the sugar

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12
Q

Describe anti conformation

A

Anti conformation has the smaller H-6 (pyrimidine) or H-8 (purine) above the sugar ring

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13
Q

Describe syn conformation

A

Syn conformation has the larger O-2 (pyrimidine) or N-3 (purine) above the sugar ring

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14
Q

What is an RNA-DNA helix?

A

When a strand of RNA folds back on itself to make a double helix

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15
Q

How is an RNA-DNA helix formed?

A

RNA contains helical regions formed by intramolecular base pairing

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16
Q

When can RNA form a double helix?

A

During reverse transcription of viral RNA
Transcription of DNA into messenger RNA
Anti-sense therapy

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17
Q

Name 5 drugs that can interact with DNA

A 
Intercalating agents
Topoisomerase poisons
Alkylating agents
Chain cutters
Chain terminators
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18
Q

What are intercalating agents?

A

Molecules which may insert themselves between bases in the DNA helix causes a frameshift mutation during replication

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19
Q

Describe the structure of intercalating agents

A

They contain heteroaromatic structures to fit between the bases

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20
Q

How do intercalating agents stay in between the DNA bases?

A

Held in position by Van der Waals interactions

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21
Q

Name 3 intercalating agents

A

Proflavine - antibacterial
Quinine - anti-malarial
Chloroquinine - anti-malarial

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22
Q

What is Doxorubicin?

A

A highly effective anti-cancer drug

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23
Q

How does Doxorubicin work?

A

It approaches the major groove of the DNA and intercalates using its planar tricyclic structure
Its amino group (NH3+) within the sugar can interact with the phosphate backbone
Hinders the normal action of topoisomerase II (enzyme involved in replication) by stabilising the enzyme-DNA complex = DNA strand stays broken
Does not inhibit the enzyme, only hinders, so = poison

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24
Q

What is Topoisomerase II?

A

An enzyme involved in DNA replication

Catalyses supercoiling

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25
Q

What is the purpose of supercoiling?

A

Allows the DNA to have a more compact structure so it can fit into the nucleus

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26
Q

How does supercoiling occur?

A

It requires 1 stretch of the DNA to cross over another

This process is catalysed by topoisomerase II

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27
Q

Name a non-intercalating drug

A

Fluroquinolones

28
Q

How do fluoroquinolones work?

A

The binding site for the drug appears only after DNA has been cleaved by the topoisomerase enzyme
It forms a planar core which stacks through Van der Waals interactions - keeping DNA strands apart & broken
Substituents at C6 and C7 positions can bind to the enzyme
Carbonyl oxygen can form H bonds with DNA

29
Q

What are alkylating agents?

A

Highly electrophilic molecules which react with nucleophlic groups (N) within the heterocyclic DNA bases

30
Q

What type of cross-links can alkylating agents form onto the DNA?

A

Inter-strand crosslink = disrupts replication and transcription by hindering separation of strands
Intra-strand crosslink = masks DNA structure from enzymes involved in replication and transcription

31
Q

What is a potential issue with the use of alkylating agents?

A

They can react with other nucleophilic groups in the body so lack selectivity and often have toxic side effects

32
Q

Inter strands = cross both strands

Intra strands = crosslinks 2 bases in 1 strand

A

a

33
Q

How do nitrogen mustards work as anti-cancer agents?

A

By forming crosslinks within DNA structures (intra and inter)

34
Q

How do nitrogen mustards (alkylating agents) react?

A

SN2 reaction mechanism
Lone pair of the nitrogen attacks the carbon and halogen LG is lost
Very reactive species formed, N has a positive charge
N on nucleotide attacks molecule and breaks the C-N bond
2nd CN bond is formed when N attacks Cl again, and another nucleotide attacks the molecule to break the bond
Crosslink is formed with DNA

35
Q

How can the toxicity of alkylating agents be reduced?

A

By ensuring the active species if formed during metabolism

36
Q

How does Nitrosoureas work as an anti-cancer drug??

A

It decomposes spontaneously to form an alkylating agent and carbamylating agent

37
Q

What is a carbamylating agent?

A

Binds and inactivates proteins

38
Q

How does Busulfan work as an anti-cancer drug?

A

Forms inter-strand crosslinks following an Sn2 mechanism

39
Q

How does Cisplatin work as an anti-cancer drug?

A

Once it is in the cellular environment, its 2 chloride substituents are displaced by water molecules
The active species then forms intra-strand crosslinks in regions containing adjacent guanine bases
Attachment of the drug disturbs the hydrogen bonding between the heterocyclic bases resulting in local unwinding of the helix

40
Q

What are ‘chain cutters’?

A

Drugs that cleave the DNA and prevent DNA ligase (enzyme) from repairing the damage
Works through a radical mechanism resulting in oxidative cleavage of the DNA structure

41
Q

What are chain terminators?

A

Molecules which inhibit DNA replication by acting as ‘false substrates’
They lack the functional groups (3’ hydroxyl/OH) required for further chain growth so incorporation into a growing DNA chain = termination
However have 3 phosphate groups attached to build on the back bone (Drug-P-P-P instead of G-P-P-P)

42
Q

What are the clinical uses of chain terminators?

A

Used as anti-viral drugs

Target reverse transcriptase in HIV

43
Q

How can gene transcription be controlled?

A

By targeting DNA base pairs
Stabilisation of the double helix will inhibit the processes involved in the transcription and ultimately protein synthesis

44
Q

What can be used to control gene transcription?

A

Hairpin polyamide structures selectively bind to specific DNA sequences
They must bind in a regulatory region to have any effect on gene expression

45
Q

Why does RNA provide an attractive drug target

A

Antisense

siRNA

46
Q

Why is RNA more difficult to target than DNA?

A

RNA is more transient

As soon as it is produced it is taken up by the ribosomes to produce proteins

47
Q

What is an oligonucleotide?

A

A short nucleic acid polymer which is designed to hybridise specifically to DNA or RNA
Usually made up of 13-25 nucleotides
Can be used in antisense therapy

48
Q

What is antisense RNA (asRNA)?

A

A single-stranded RNA which is complementary to a mRNA strand transcribed within the cell

49
Q

How does an antisense DNA oligonucleotide prevent translation?

A

Forms a DNA-RNA duplex

The ribosomes cannot process a double-stranded molecule

50
Q

Briefly describe the process of how DNA leads to the production of a protein

A

The DNA is transcribed into RNA in the nucleus
The RNA leaves the nucleus and is fed through ribosomes
The ribosomes produce chains of amino acids
These amino acids fold to form proteins

51
Q

What are the 2 modes of action of antisense therapy?

A

Steric block = highly stable DNA-RNA duplex formed so ribosome cannot separate it
Cleavage by RNaseH = cleavage of RNA strand of DNA-RNA duplex

52
Q

How does antisense therapy work?

A

Blocks translation of single strand of mRNA by causing an antisense DNA oligonucleotide to bind with it
This forms a DNA-RNA duplex which cannot be processed by the ribosomes in order to produce a protein

53
Q

List the 5 optimal characteristics of antisense therapy

A 
Duplex stability
Specificity - target a specific RNA strand
Nuclease stability
Cellular uptake
Toxicity
54
Q

How can duplex stability be measured?

A

By UV spectroscopy
A base pair = chromophore
Stacking of the base pairs = decrease in absorbance of the helical structure

55
Q

How can it be ensured that the antisense oligonucleotide will be stable in physiological environments?

A

Plot absorbance vs Temperature
Tm (peak) can be used
Body temperature = 37C so it must be stable at this temperature

56
Q

How can the antisense oligonucleotide be specific?

A

Due to the well-defined base pairing properties of nucleic acids, the antisense oligonucleotide can be designed to specifically target a particular site

57
Q

What could be the issues of designing an antisense oligonucleotide specifically to a strand of RNA?

A

Oligonucleotide too short = could lead to the targeting of other regions of RNA, not specific enough
Oligonucleotide too long = could lead to the targeting of mismatched sequences

58
Q

What is RNA interference?

A

Biological process in which miRNA molecules inhibit gene expression, typically causing the destruction of specific mRNA molecules
RNA –> miRNA –> siRNA –> mRNA destroyed

59
Q

What is micro-RNA?

A

Small double-stranded RNA molecules (RNA-RNA duplex)
Produced from larger RNA sequences by the Dicer enzyme
miRNA

60
Q

How does miRNA work?

A

miRNA produced from larger RNA sequences of by the Dicer enzyme
It then binds to a complex of enzymes known as RISC (RNA inducing silencing complex)
In the RISC, 1 strand is discarded to leaving the rest behind = the small interfering RNA sequence (siRNA), single-stranded
The active RISC recognises a complemetary mRNA, siRNA (still attached to the RISC) binds to it and induces cleavage of the mRNA
Inhibition of protein synthesis
Cleavage of viral RNA halts attack

61
Q

What is Anti-gene therapy?

A

Similar to the antisense approach but targets the DNA double helix rather than the RNA

62
Q

How does Anti-gene therapy work?

A

Introduction of 3rd strand of DNA added to double helix at the major groove = triple helix
The base pairs in DNA are capable of further hydrogen bonding = Hoogsteen base triplets

63
Q

List the 2 types of Hoogsteen base triplets which can exist

A

C+G-C

T+A-T

64
Q

Explain the C+G-C base triplet

A

It is more stable but protonation of C leads to a pH dependency
Successive stacking of C+G-C base triplets leads to a destabilisation of the helix (charges stacking)

65
Q

Explain the T+A-T base triplet

A

This base triplet does not suffer from the same problems as C+G-C but is inherently less stable

66
Q

What can be used to measure the stability of the triple helix?

A

UV spectroscopy

Absorbance vs Temperature

67
Q

List 2 problems that must be overcome in order for the Anti-gene approach to provide suitable therapeutic action

A

Delivery - oligonucleotides are highly charged species which will find it difficult to cross the cell membranes
Initial approaches could only target purine bases and not pyrimidines - so a single pyrimidine base in a stretch of purines leads to destabilisation of the helix

PM2A Spring Amy L (15 decks)

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