Biomedical Sciences: Treatment of Viral Infections (Lecture 10; Exam 2)

Antiviral drugs can stop infection only if ___.

They are given very early in infection!

(Requires specific diagnosis and prompt treatment.)

Why are viral infections so hard to treat?

• Diverse life-cycles

• Hard to target (side effects are common)

• Drugs are usually “virus'-specific”

• Resistance to antivirals can occur very rapidly.

  • ESPECIALLY by RNA viruses.

True/False: DNA viruses evolve more slowly than RNA viruses.

True.

Why do RNA polymerase have a higher mutation rate than DNA polymerase?

They do not have a correction mechanism; lack proofreading.

Targets for Antivirals:

• Stop the viral replication cycle.

• Must target specific viral component to limit toxicity.

Antiviral Target: Attachment

Interaction of a viral attachment protein with its cell surface receptor.

What do neutralizing antibodies do?

Bind and coat the virion.

What are examples of neutralizing antibodies?

• HBIG

• VZIG

• Rabies IG

• Monoclonals against SARS-CoV-2

What are receptor antagonists?

Peptides or sugar analogues of the cell receptor, compete for binding to viral attachment proteins.

What is the receptor antagonist for HIV?

CCR5 antagonist.

What does the CCR5 antagonist do?

Block the CCR5 coreceptor on immune cells to prevent HIV cells from entering and infecing them.

Injection of neutralizing antibodies against SARS-CoV-2 after positive COVID-19 test is an example of what kind of immunization?

Artificial passive.

Penetration and Uncoating:

The 2nd and 3rd steps: the virus crosses the host cell membrane and strips away its protein coat to release its genetic material.

What are fusion inhibitors?

A class of antiviral medications that block a virus from entering and infecting host cells.

Examples of fusion inhibitors:

• Docosanol (Abreva - OTC)

• Enfuvirtide (fuzeon)

What does Enfuvirtide inhibit?

HIV.

What does Docosanol inhibit?

HSV.

What are prime targets for most antiviral drugs?

• Viral DNA polymerases

• Reverse transcriptases

What are nucleoside analogues?

A man-made or modified molecule that looks like a natural nucleoside but has a slight structural difference in its sugar or base.

• Modifications of the 4 bases (AGTC)

What do nucleoside analogues target?

Target viruses with RTase or encoding their own DNA polymerase.

What do RNA nucleoside analogs do?

• Chain termination

• Induces mutations

• Leads to non-functional genomes.

Examples of RNA nucleoside analogs:

• Remdesivir

• Molnupirivir

Remdesivir (nucleoside analogue)

Intravenously administered.

• Given to hospitalized patients

• Little to no benefit

Molnupirivir (nucleoside analogue)

Orally administered ribonucleoside analog that inhibits the replication of SARS-CoV-2, given to non-hospitalized patients.

What phosphorylates Acyclovir?

Viral thymidine kinase.

Why is acyclovir able to be taken up by the cell?

Because it is unphosphorylated.

What does viral thymidine kinase do?

Phosphorylates acyclovir.

What virus is reistant to acyclovir?

HSV.

What is Phosphonoformate?

Also called Foscarnet;

Pyrophosphate analog; blocks nucleoside binding site in polymerase.

What does Phosphonoformate (Foscarnet) do?

Inhibits HSV DNA polymerase; does not terminate replicating DNA.

What do non-nucleoside reverse transcriptase (RT) inhibitors do?

Block active site of nucleotide binding.

Integrase Inhibitors

A class of prescription medications used to treat and prevent HIV;

Stop retroviruses from inserting their viral DNA into a host cell’s chromosomes.

What are interferons?

Signaling proteins released by host cells in response to pathogens like viruses to help protect nearby uninfected cells.

How do interferons stop a virus?

By promoting inhibition of protein synthesis in an infected cell.

(Force an antiviral state of a patient’s cells.)

(interferon therapy is used as a last resort - can be very dangerous.)

What are Neuraminidase Inhibitors?

A class of antiviral medications used to treat and prevent influenza caused by both influenza A and influenza B viruses.

What are Protease inhibitors?

A class of antiviral medications that block specific enzymes called proteases.

(Prevents viruses from making copies of themselves.)

What is the protease inhibitor for SARS-CoV-2

Paxlovid.

Protease Inhibitors for HIV:

• Saquinavir

• Ritonavir

• Indinavir

Advantages of Combination Therapy:

• More effectively inhibit viral replication

• Decreases likelihood of development of drug resistance

• Combinations may have additive or synergistic effects.

  • May allow lower doses of highly toxic drugs.

• Ideal treatment will prevent viral replication and survival of resistant virions.

There are only about 100 antivirals available in the US. What type of infection do most of these target?

Persistent infections.

What do non-nucleoside polymerase inhibitors do?

Are pyrophosphate analogs;

Blocks nucleoside binding site in polymerase.

What do non-nucleoside reverse transcriptase inhibitors do?

Block active side of nucleotide binding.

What are Integrase inhibitors?

A class of prescription medications used to treat and prevent HIV by stopping the virus from multiplying.

What are synthetic inteferons?

Lab-made versions of natural proteins your immune system uses to fight viruses and cancer.