W8 Pharmaceutical Chemistry of antiviral drugs

Question 1

Chemistry of DNA and RNA

Answer 1

Deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) are polymers of nucleotides

Their building blocks are made of 3 elements:

Question 2

Nucleoside drugs MoA

Answer 2

ALL nucleoside drugs require metabolic activation in their target cell to the
bioactive phosphate forms:

Nucleosides can be phosphorylated by host or viral kinases (if present)

Question 3

AZT: Reverse Transcriptase Inhibitor
What is its moA?

Answer 3

1-Similar to the normal deoxythymidine triphosphate
building block →bind to viral RT and inhibit it
(COMPETITIVE INHIBITOR)

2-Incorporate into the growing proviral DNA chain → sugar unit lacks the required OH in 3′ of the sugar ring
→nucleic acid chain cannot be extended any further
CHAIN TERMINATOR

Question 4

Acyclovir (ACG)

Answer 4

Aciclovir is an Acyclic Nucleoside Analogue which requires metabolic activation

-Similar to the normal deoxyguanosine
triphosphate building block → binds to and
inhibits the viral DNA polymerase
(COMPETITIVE INHIBITOR)

2-Incorporate into the growing DNA
chain → sugar unit lacks the required
OH in 3′ of the sugar ring →nucleic acid
chain cannot be extended any further
CHAIN TERMINATOR

Question 5

Acyclovir analogue

Answer 5

Valacyclovir (sold as hydrochloride salt)
Amino acid ester prodrug → increased water solubility →
increased GI absorption → bioavailability is 54%.
HSV-1 and 2, VZV, HCMV
L-Valyl
Exhibits antiviral activity only after metabolism (hydrolysis) in the intestine or
liver to acyclovir followed by conversion to the triphosphate
A specific binding interaction is involved in the absorption process → actively
transported by transport proteins in the gut, valine allows the prodrug to be
recognized and bound by these proteins
Poorer absorption if D-valine is used
Similar polarity and ionization to acyclovir → no more able to cross the cell membranes of
the gut wall by passive diffusion than acyclovir.

Question 6

Problems of Nucleoside Drug

Answer 6

Often) poor metabolism to the active triphosphates
Rapid deactivation
Active transport needed
Toxicity common (due to similarity to human nucleosides)
Emergence of resistant virus
-transporter
-kinase
-polymerase

SOLUTION: prepare monophosphate drugs, so the first slow step is skipped and if TK absent, the drug works anyway

Question 7

ProTide Approach

Answer 7

Lipophilic (increase passive diffusion into cells of monophosphate nucleotide)
Stability in plasma
Hydrolysis in cells (easily release of the monophosphate nucleotide)
Byproducts non-toxic

Question 8

ProTide MoA

Answer 8

Cleavage the ester group of amino acid

Internal cyclization to remove the
phosphate OH protecting group…Not proved!!!

Question 9

Advantages of this prodrug approach

Answer 9

Advantages of this prodrug approach:

• Helps in circumventing the first and inefficient rate-limiting phosphorylation
  step of nucleosides
• Increases the passive diffusion into cells of the monophosphate nucleotide
• Protects the labile phosphate from cleavage
• After activation, it releases non toxic by-products
• Can be applied to bot phosphate and phosphonate nucleotide derivatives

Question 10

Non-nucleoside Reverse Transcriptase inhibitors:
What are some examples?

Answer 10

Nevirapine
Delavirdine