Medicinal Chemistry of Antiviral Drugs: Part 1

What is a virus composed of?

A virus is composed of a nucleic acid strand and associated proteins.

Can viruses reproduce on their own?

No, viruses attach to a host cell to reproduce.

What happens after a virus recognizes and binds to a host cell receptor?

The virus undergoes penetration and then uncoating.

What is the difference between early and late transcription/translation in a virus life cycle?

Early transcription/translation occurs first to make initial proteins; late occurs later to produce structural proteins.

Why is it hard to design effective antiviral drugs?

Viruses mutate easily, have intracellular replication, and rely on host enzymes.

What does neuraminidase do in influenza infection?

It hydrolyzes the bond between the virus and the host cell, allowing release.

What does the M2 protein channel in influenza do?

It allows protons to enter the virus, creating an acidic environment needed for uncoating.

Why is targeting the M2 protein effective against influenza?

Blocking M2 prevents acidification, which stops viral uncoating and replication.

What are examples of M2 inhibitors?

Amantadine and Rimantadine.

How do M2 inhibitors work?

They block the proton channel, preventing acidification inside the virus.

What are key structural features of M2 inhibitors?

They are symmetrical, tricyclic, and have an amine group, allowing ionic and hydrophobic interactions.

What kind of genetic material does the influenza virus have?

Single-stranded RNA.

What type of interaction occurs between M2 inhibitors and the viral protein?

Ionic interaction between nitrogen and aspartate, and hydrophobic interaction between the cage/tricyclic core and nonpolar residues.

What happens if you replace Asp44 with a nonpolar residue in M2 protein?

The virus may become resistant or the interaction may be altered.

What is the role of hemagglutinin (HA) in influenza infection?

HA helps the virus attach to the host cell by binding to sialic acid on the cell surface.

What is the function of neuraminidase (NA) in influenza?

NA hydrolyzes the bond between hemagglutinin and sialic acid, allowing the virus to be released from the host cell.

Why is sialic acid an important target in drug development?

It is polar, sugar-like, and its structure can be mimicked to inhibit neuraminidase.

What type of drug can inhibit neuraminidase?

Drugs that mimic the structure of sialic acid to compete with its binding.

What kind of bonds do neuraminidase inhibitors form?

Hydrogen bonds and ionic bonds with residues in the active site of neuraminidase.

What does oseltamivir do and how is it processed in the body?

It is a prodrug that is converted by esterases into an active metabolite to inhibit neuraminidase.

What do all neuraminidase inhibitors have in common structurally?

They all contain ring structures and mimic the structure of sialic acid.

What are examples of neuraminidase inhibitors?

Zanamivir (Relenza), Oseltamivir (Tamiflu), Peramivir (Rapivab).

What is the function of reverse transcriptase in HIV?

It converts viral RNA into DNA.

What does the HIV integrase enzyme do?

It integrates the newly made viral DNA into the host genome.

What happens to HIV RNA after it is integrated into the host DNA?

It becomes part of the host genome and is used to produce viral proteins.

What are polyproteins in the HIV life cycle?

They are inactive proteins synthesized by the host, which must be cleaved into active forms.

What is the function of HIV protease?

It cleaves inactive polyproteins into active viral components needed for replication.

What happens if HIV protease is inhibited?

Inactive polyproteins are not cleaved, preventing the virus from maturing and replicating.

What is the function of HIV protease?

It cleaves viral polyproteins into functional viral proteins essential for replication.

Why is precise cleavage by HIV protease important?

If it cuts in the wrong spot, the resulting product is inactive and the virus can't mature.

What is the significance of the P3 and P2 sites in the protease substrate?

These sites are mimicked by drugs to block the protease from cleaving the actual polyprotein.

What are S1 and S1’ in HIV protease?

They are binding pockets for the substrate; due to the dimeric nature of the enzyme, S1 and S1’ are equivalent.

Why is HIV protease referred to as an aspartic protease?

Because it uses two aspartate residues (one from each monomer) in its catalytic mechanism.

What structural motif is conserved in HIV protease’s active site?

A conserved Asp-Thr-Gly motif is present and required for activity.

What is the role of hydroxyethylamine in HIV protease inhibitors?

It mimics the transition state and forms hydrogen bonds with aspartate residues in the active site.

Why is the hydroxyl group important in HIV protease inhibitors?

It must be in the right formation to hydrogen bond with both catalytic aspartate residues.

What structural feature is inserted between the S1 and S1’ sites in protease inhibitors?

A phenyl group, which helps with binding affinity.

What is the purpose of bulky protecting groups in protease inhibitors?

They increase activity by protecting the molecule from degradation.

How does the addition of pyridine or urea affect protease inhibitors?

They increase polarity and water solubility, improving the drug's pharmacokinetics.

Why is the phenyl group significant in HIV protease inhibitors?

It fits into the S1/S1’ pocket and improves binding.

What do all effective HIV protease inhibitors have in common structurally?

They include a hydroxyl group for binding and a phenyl group for fitting into the enzyme pockets.

How do protease inhibitors stop HIV replication?

By preventing the cleavage of polyproteins, stopping the formation of functional viral proteins.

What is a common structural feature of many HIV protease inhibitors?

A phenyl ring with a hydroxyl group that fits between S1 and S1’ and interacts with aspartate residues.

How are most HIV protease inhibitors metabolized?

By cytochrome P450 enzymes (CYP450).

What is the function of the phosphate group in fosamprenavir?

It makes the drug a prodrug that is activated in the body.

Why is darunavir considered a strong protease inhibitor?

It binds better due to the Eis-tetrahydrofuryl group that fills the hydrophobic S2 pocket and forms strong H-bonds.

Why is ritonavir used in combination with other protease inhibitors?

It inhibits CYP3A4, protecting other protease inhibitors from being metabolized.

What is unique about ritonavir's activity as a protease inhibitor?

It has low activity by itself but boosts other drugs by inhibiting CYP enzymes.

Why is fosamprenavir considered a prodrug?

It is converted in the body into the active form, improving solubility and bioavailability.

How does oseltamivir work as a neuraminidase inhibitor?

It is a prodrug converted by esterases into an active metabolite that mimics sialic acid.

How does zanamivir differ from oseltamivir?

Zanamivir already has a free carboxylic acid group and does not require activation by esterases.

What is the role of the dual aspartate residues in HIV protease?

They are crucial for cleaving the polypeptide into active proteins.

How do neuraminidase inhibitors like zanamivir and oseltamivir work?

They bind to the same active site as sialic acid, blocking neuraminidase function.