Antivirals MedChem

What is a diagram showing different viral families? (COVERED ELSEWHERE)

What is an overview for how viruses replicate?

Adhere to cell surface or entry into cell via penetration of cell wall, release DNA/RNA when inside and enters the nucleus, incorporates their DNA into genome and encapsulates into a protein before being released again

What are examples of NRTIs?

Deoxyguanosine, aciclovir, zidovudine, deoxythymidine

What does NRTI stand for?

Nucleoside reverse transcriptase inhibitor

What class are most antivirals part of?

NRTIs

What properties do most NRTIs have?

Can be phosphorylated - usually triphosphorylated, synthetic analogues of nucleosides

How do NRTIs work?

Selectively inhibit viral reverse transcriptase, when triphosphorylated are incorporated into viral DNA and doesn’t encode for DNA repair proteins - leads to chain termination

What functional groups does zidovudine contain?

Lipophilic azide

What NRTI is zidovudine an analogue of?

Deoxythymidine

What are examples of deoxyguanosine analogue antivirals?

Aciclovir, valaciclovir, penciclovir, famciclovir

What amino acid residue does valaciclovir have?

Valine residue

What happens to the valine residue when valaciclovir is metabolised?

Cleaved off and leaves the hydroxyl group to be phosphorylated

What is a potential advantage of using penciclovir instead of aciclovir?

Retained in cell longer

What antiviral is a prodrug of penciclovir?

Famciclovir

What part of famciclovir needs to be cleaved to become active?

Ester groups

Why are prodrugs of deoxyguanosine favourable?

Aids absorption

What antivirals are used against human cytomegalovirus?

Ganciclovir, valganiciclovir, letermovir, cidofovir

What antivirals are commonly used for herpes simplex/zoster infections?

Deoxyguanosine analogues

What is the structural difference between ganciclovir and aciclovir?

Ganciclovir has an additional primary alcohol group

What type of antiviral is letermovir?

Non nucleoside inhibitor of DNA-terminase complex

What is cidofovir a derivative of?

Cytidine

What is a benefit of cidofovir?

Already phosphorylated

How does letermovir work?

Prevents processing of long, repeating viral DNA into individual mature viral genomes and prevents release of new virions

What antivirals are used against Hep B?

Entecavir, lamivudine, adefovir

What functional group is present in lamivudine that makes it very active for HIV?

Oxygen and Sulphur inside a carbocycle

What nucleotide base is entecavir a derivative of?

Guanosine

What nucleotide base is lamivudine a derivative of?

Cytosine

What nucleotide base is adefovir a derivative of?

Adenosine

Why is entecavir not used to treat hepatitis B in HIV patients?

Risk of selecting for resistance to lamivudine

What can tenofovir be formulated as?

Fumarate salt of tenofovir alafenamide or tenofovir disoproxil

How does tenofovir work?

Inhibits viral DNA polymerase by causing chain termination

What is tenofovir an analogue of?

Acyclic nucleotide analogue of AMP

What are the characteristics of tenofovir alafenamide?

Isopropyl ester, alanine residue and phenol increase uptake of the cell

What antivirals are used to treat Covid-19?

Nirmatrelvir, remdesivir, molnupiravir

What is combined with nirmatrelvir to increase its bioavailability?

Ritonavir

What does nirmatrelvir inhibit?

Inhibits viral 3C-like protease found in coronaviruses

How do remdesivir and molnupiravir act?

Both inhibit viral RNA-dependant RNA polymerase

What properties does remdesivir have?

Alanine based moeity, furan ring and nitrile in position 1

What is the only change in molnupiravir from a nucleotide?

N-OH group on the N containing ring

What is remdesavir an analogue of?

Adenosine monophosphate analogue, prodrug

How does the hepatitis C virus replicate?

• Virus entry into the cell

• Fusion and uncoating, sRNA released

• Translation into single polypeptide

• Cleave of polyprotein by NS3 protease, gives 3 structural and 7 non=structural proteins

• Forms membrane-bound complex of viral and host proteins

• Replication/transcription dependant on RNA-dependant RNA polymerase

What is the key to viral replication and assembly in Hep C?

NS5A

What indicates the therapeutic regime for Hep C?

Genotype of infection

What are examples of NS3/4A inhibitors for Hep C?

Voxilaprevir, paritaprevir

What are examples of NS5A inhibitors for Hep C?

Velpatavir, ombisavir

What NS5A inhibitor can be used for all genotypes of Hep C?

Pibrentasvir

What are examples of NS5B inhibitors for Hep C?

Sofosvucir, dasabuvir

What is an example of an auxillary treatment for Hep C?

Ritonavir

What are the characteristics of rivavirin?

1,2,4 triazole which is triphosphorylated and incorporated into DNA

What is ribavirin?

Nucleoside analogue that acts in same way as other nucleoside DNA polymerase/reverse transcriptase inhibitors

What are the characteristics of paritaprevir?

Sulfonamide region binds into active site, rest of molecule positions into the active site

Where is NS4A found in Hep C?

ER membrane and associates with NS3 protease

What is used to increase paritaprevirs bioavailability?

Ritonavir

What should inhibit protein cleavage in Hep C?

Peptide/peptidomimetic in NS3 active site - peptide that wouldn’t be cleaved!

What is glecaprevir used in combination with to be active against all phenotypes of Hep C?

Pibrentasvir - includes strains resistant to 1st gen NS3 inhibitors

What are examples of me too NS3/4A inhibitors?

Grazoprevir, voxilaprevir, glecaprevir

What does NS5A exist as?

Homodimer - crucial for replication of HCV

What was the first discovered NS5A inhibitor?

Daclatasvir

What key functional groups did daclatasvir contain?

Imidazole and prolene regions

How was daclatasvir discovered?

Serendipity in SAR studies

What is a summary for discovery of daclatasvir?

• Initial screening contained imidazole-proline moeity

• SAR study done showed oxygen to methylene has a large difference in activity

• Compound 8 decomposed in common solvent of DMSO, unstable in media

• Symmetrical analogues then investigated

What part of ombitasvir has potential for activity?

Methylester

Why is pibrentasvir hard to formulate?

Large size - poor solubility

What are some examples of non-symmetrical NS5A inhibitors?

Elbasvir, ledipasvir, velpatasvir

What is the issue with the non-symmetrical NS5A inhibitors?

Difficult to synthesise

What are NS5B inhibitors always used as?

Combination!

What are examples of NS5B inhibitors?

Sofosbuvir, dasabuvir

What are sofosbuvir and dasabuvir derivatives of?

Uridine

What is sofosvbuvir a prodrug of?

NRTI - converted to triphosphate in the liver

What is dasabuvir?

NNRTI that binds to an allosteric site in palm domain of HCV NS5B