Med Chem Unit II: Set D, Viruses

Why is RNA more susceptible to reactions than DNA?

-single-stranded

-labile

-must be linear for translation

What is the goal of nucleoside based antiviral agents?

halting polymerase activity

Provide one of the two MOAs of acyclic nucleoside analogs.

1. selective activation and inhibition of polymerase enzymes

2. incorporation into DNA terminates chain elongation

How does neuroaminidase connect with viruses?

facilitates virion release by cleaving sialic acid

Which should have better binding: an original substrate or a TS mimic?

TS mimic

What are common structural components of neuraminidase inhibitors?

6 membered heterocycle with sp2-sp3 bond, CO2X substituent

How do nucleoside analogs prevent nucleic acid replication?

alter conformation so that polymerase can't bind which compromises elongation

How do famciclovir and penciclovir inhibit viral polymerase?

activation leads to inhibition of DNA polymerase

What is the infection cycle for HIV?

1. viral entry

2. reverse transcription

3. genome integration, viral RNA synthesis

4. viral protein translation

5. viral proteases cleave into functional proteins

6. assembly, budding, and release

What are common targets for chemotherapy for HIV? (name 2)

1. reverse transcriptase

2. integrase

3. HIV protease

4. entry process

What is the MOA of HIV Integrase?

chelates catalytic metal in integrase which inhibits the insertion of viral DNA into host DNA

What process do proteases use to cleave peptide bonds?

hydrolysis

What is the significance of HIV protease?

facilitates PTMs of immature proteins into structural proteins

What is the mechanism of HIV protease?

1. deprotonation of water by aspartate 25

2. hydroxide ion attacks carbonyl C

3. electrons flow back to deprotonate another molecule of aspartate 25

4. aspartate 25 deprotonates OH to break down the tetrahedral IM by forming carbonyl; C-N bond breaks to deprotonate another Asp 25

Saquinavir, indinavir, nelfinavir, and lopinavir are examples of what?

peptidomimetic protease inhibitors

What is the MOA of enfuvirtide (HIV 1 drug)?

inhibits fusion of viral particle to host T lymphocyte by interacting with gp41

What is the MOA of maraviroc (HIV 1 drug)?

binds CCR5 chemokine coreceptor to block diffusion of HIV to cells

Which forms of hepatitis are spread by contaminated water and food?

Hep A and E

Which forms of hepatitis are spread by infected blood or unprotected sex?

Hep B and D

Which form of hepatitis is primarily spread by contact with infected blood?

Hep C

How do entecavir, telbivudine, and adefovir dipicoxil act as anti hepatitis B agents?

replication inhibitors

What is the role of NS3-4A protease in the life cycle of Hepatitis C?

cleaves HC polyprotein into smaller functional proteins

What is the role of NS3-4A inhbitors in the life cycle of Hepatitis C?

prevent processing of HCV polyprotein to block replication

What is pharmacophore for anti hep C agents?

double ketone next to NH2/HNR group

What is the target of the anti-hep C agents boceprevir and telaprevir?

NS3/4A

What is of note about the boceprevir and its interaction with serine?

doesn't have a leaving group so it forms a stable complex intermediate

What drug first made hepatitis curable? What does it target?

sofosbuvir, targets NS5A

MOA: binds DNA and acts as replication and polymerase inhibitor

What are some of the processes that NS5A is involved in within the hepatitis C life cycle?

replication and assembly processes

What is the MOA of the NS5A inhibitor ledipasvir?

blocks viral replication and assembly by binding and preventing other things from binding to DNA