antiviral agents

lecture given 4/7/2026

viruses

very small infectious agents- require host cells to survive

obligate intracellular pathogens- uses host machinery (difficult drug target)

treatment varies- short term vs long term

what are drug targets for antivirals?

replications steps- entry, replication, release

most antivirals are virustatic so they only work during active virus replication

what are the components of basic viral structure?

nucleic acid- viral genetic material (DNA or RNA)

capsid- protein shell that protects the genetic material

nucleocapsid- capsid + nucleic acid

envelope (if present)- outer lipid layer, makes virus easier to disrupt

glycoproteins- surface proteins that bind host cells, allow entry

DNA viruses

make mRNA from DNA (usually using host enzymes)

most replicate in the host cell nucleus, most use host cell enzymes to make mRNA from viral DNA

RNA viruses

must convert RNA into mRNA

most replicate in the cytoplasm, must encode or carry viral enzymes to make mRNA

RNA +

already mRNA and is translated immediately

RNA -

must first be converted to + RNA

requires viral RNA polymerase

reverse transcription (RT)

RNA to DNA step

used by HIV (RNA virus) and HBV (DNA virus with RNA intermediate)

major drug target

what are examples of DNA viruses?

herpesviruses, adenoviruses, papullomaviruses, hepatitis B

what are examples of RNA viruses?

influenza, coronaviruses, HIV, hepatitis C

why is influenza virus an exception to RNA viruses?

it uses the host cell nucleus

herpes simplex virus 1 (HSV1)

DNA herpesvirus

primary herpetic gingivostomatitis (painful, diffuse oral lesions)

recurrent cold sores (labial herpes)

herpes simplex virus 2 (HSV2)

DNA herpesvirus

genital herpes

varicella-zoster virus (VZV)

DNA herpesvirus

chickenpox (primary infection)

shingles (reactivation → dematomal pain + vesicles)

cytomegalovirus (CMV)

DNA herpesvirus

severe disease in immunocompromised (retinitis, colitis, esophagitis)

what are the key concepts of herpesvirus (DNA virus)

disease = active viral replication

after infection the virus becomes latent (lifelong)

reactivation leads to recurrent disease

replication of herpesvirus (DNA virus)

virus enters cell, uncoats, and DNA goes to nucleus

viral DNA becomes mRNA to proteins using host machinery

viral DNA replicated by viral DNA polymerase

what are the drug targets of herpesvirus (DNA virus)?

viral DNA polymerase (selective)

some viruses activate drugs vial viral enzymes

drugs work only during active replication (not latency)

anti herpes agents

require phosphorylation by viral thymidine kinase (TK), then host enzymes activate triphosphate

only infected cells activate the drug

what is the mechanism of action of anti herpes agents?

inhibits viral DNA polymerase

drug-TP enters the nucleus and competes with dGTP at viral DNA polymerase, it gets incorporated into viral DNA

without 3’-OH there is chain termination and viral DAN synthesis stops and the virus cannot replicate

what are examples of anti herpes agents?

acyclovir (ACV), valacyclovir (ACV prodrug, better absorption and longer half life), famciclovir (similar)

what are the methods of resistance to ACV?

decreased or absent thymidine kinase (TK) (most common)- drug is not actived and becomes ineffective

altered viral DNA polymerase- drug cannot bind effectively and there is reduced activity

what should you do if virus becomes resistant to ACV?

use drugs that bypass activation

cidofovir- activated by host enzymes only

foscarnet- no activation required, direct polymerase inhibitor

when do we use other anti herpes agents like ganiciclovir, cidofovir, or foscarnet

CMV infections or acyclovir resistant HSV/VZV

ganciclovir

similar to acyclovir (nucleoside analog)

activated by CMV viral kinase (UL97)

main drug for CMV

side effects- bone marrow suppression (cytopenia) leads to infection and bleeding risk

cidofovir

nucleotide analog (already monophosphate)

activated by host enzymes only- works even if viral TK is absent

mechanistically weaker, still has 3’-OH, but chain termination still occurs

foscarnet

direct viral DNA polymerase inhibitor

pyrophosphate analog, blocks pyrophosphate binding site of the polymerase, inhibiting chain elongation

no activation required, already active as given

used for resistant viruses (very nephrotoxic, also electrolytes)

respiratory syncytial virus (RSV)

-ssRNA virus

causes respiratory infections in infants (winter outbreak)

~150,000 hospitalizations and ~100-500 deaths/year

what drugs are used to treat RSV?

palivizumab, ribavirin

palivizumab

monoclonal antibody against RSV

blocks viral entry into host cells

used for prophylaxis (NOT TREATMENT)

high risk infants (premature babies, congenital heart disease)

ribavirin

inhibits viral RNA synthesis of RSV

rarely used clinically

human papillomavirus (HPV)

dsDNA virus

causes warts and associated with oropharyngeal and cervical cancer

what is the treatment for human papillovirus?

no antiviral drugs that eliminate HPV

treatmetn targets lesions, not the virus

imiquimod

imiquimod

topical (cream) immune response modifier for HPV lesions

activates local innate immunity which stimulates host immune response

it is not a classic antiviral because it does not inhibit viral replication

HPV vaccine

prevention for HPV

prevents ~90% of HPV infections and HPV related cancers

tldr on HPV

no antivirals → treat lesions (remove or immune stimulation) + vaccinate

what are the key patterns of viral hepatitis?

acute, self limiting

chronic infection possible

which hepatitis infections are acute and self limiting and how are they transmitted?

HAV, HEV

fecal-oral transmission

which hepatitis infections are chronic and how are they transmitted?

HBV, HCV

blood and body fluids

can lead to cirrhosis and liver cancer

what is special about HDV?

it requires HBV to replicate

what is the clincal relevance of chronic HBV and HCV?

can cause liver disease and affect drug metabolism and bleeding risk

how can HBV be prevented?

vaccine! no vaccine for HCV though

t/f HBV is curable with antivirals but HCV is controlled, not cured (aka long term suppression)

false- opposite

acute infection with HBV

<6 months

osten self-limited

chronic infection with HBV

>6 months

risk depends on age- infants have high risk of chronic infection while adults have lower risk

can lead to cirrhosis or hepatocellular carcinoma

what happens in the host cell nucleus during HBV infection?

partially dsDNA (one complete strand, one incomplete strand)

in host cell nucleus the DNA is repaired and completed using host enzumes

forms a cccDNA (covalently closed circular DNA)

stable nuclear reservoir in hepatocytes

cccDNA is transcribed to RNA including pgRNA

what happens during replication of HBV?

pgRNA (RNA intermediate) is reverse transcribed into DNA

what is the clinical consequence of HBV lifecycle?

cccDNA persists so the virus is not eradicated

can reactivate (esp likely if HDV is present)

NRTIs (nucleos(t)ide reverse transcriptase inhibitors)

tenofovir (TDF, TAF), entecavir

inhibit viral DNA polymerase (reverse transcriptase activity)

nucleos(t)ide analogs, no 3’-OH group is incorporated into DNA strain which terminates the chain and decreases viral DNA synthesis

what is the goal of HBV drug targets?

suppress viral replication (HBV DNA is decreased to undetectable)

no cure! virus is never eradicated because cccDNA persists in nucleus

tenofovir

TDF, TAF (prodrugs)

active against HBV and HIV

TAF is preferred because less renal and bone toxicity and higher intracellular drug levels

entecavir

HBV only, very potent, low resistance

chronic hepatitis C

major cause of chronic liver disease

high rate of chronic infections (~70-85%)

curable! sustained virologic response (HCV RNA is undetectable in blood)

what therapy was used for HCV in the past?

interferon + ribavirin

modest efficacy, significant toxicity

what is the current therapy for HCV?

oral direct-acting antivirals (DAAs)

>95% cure rates, short duration, well tolerated

what are the key steps in the HCV life cycle?

viral RNA is translated into one long polyprotein

nonfunctional polyprotein is then cleaved into functional proteins (viral protease)

viral RNA is then replicated by RNA polymerase (NS5B)

there is no stable cccDNA reservoir

what are the drug targets for HCV?

prevent polyprotein processing so they target viral non-structural proteins

NS3/4A protease inhibitors- block polyprotein cleavage

NS5A inhibitors- block replication and assembly

NS5B polymerase inhibitors- block RNA replication

DAAs

direct acting antivirals, used in combo therapy to cure HCV

previr

NS3/4A protease inhibitor

stops the polyprotein of HCV from being processed

NS3/4A are protease and cofactor, they cut the polyprotein

-asvir

NS5A inhibitors

N5A organizes replication machinery and virion production

RNA replication and virion assembly fail

-buvir (sofusbuvir)

NS5B polymerase inhibitor

N5B copies viral RNA

terminates chain formation- RNA synthesis stops

t/f HCV DDAs are oral therapy with a short duration (8-12 weeks) with >95% cure rates

true

interferons for HCV

immune signaling proteins (cytokines)

act on the host, enhancing host’s antiviral responses

induce the production of enzymes that inhibit viral mRNA translation

do not directly target virus

synthesized by mammalian cells; produced by recombinant DNA

what are the side effects of interferons and ribavirin (legacy therapy for HCV)?

flu-like symptoms, fatigue, mood changes

hemolytic anemia

ribavirin

nucleoside analog antiviral

influenza virus type A

RNA virus, more severe, found in humans and animals

influenza virus type B

RNA virus, milder, humans only

entry of influenza virus

binds sialic acid (host cell surface receptor) via hemagglutinin (H)

enters by endocytosis

uncoating of influenza virus

M2 channel allows H+ entry

uncoating and release of viral RNA

*this is a drug target (M2 inhibitors)

replication and transcription of influenza virus

viral RNA is replicated and transcribed

*this is a drug target (polymerase inhibitors)

assembly of influenza virus

viral RNA and proteins assemble

release of influenza virus from cell

neuraminidase (N) cleaves sialic acid which releases virus

*this is a drug target (neuraminidase inhibitors)

M2 inhibitors

rarely used (influenza)

block viral M2 protein (proton channel)

prevent uncoating and the viral RNA is not released

resistance is common

neuraminidase inhibitors

oseltamivir

main drug for influenza

block neuraminidase- prevent new viral release from infected cells

this traps the virus and decreases viral spread and duration/severity

one drug is available as an inhalation

endonuclease inhibitors

anti influenza agets

blocks cap-dependent endonuclease which prevents viral mRNA synthesis (cap snatching)

no viral protein production

cap snatching

virus steals 5’ cap from host mRNA to make its own mRNA recognizable to ribosomes

stats on HIV/AIDS

40.8 million people living with HIV (+20% relative to 2010)

less transmission, far fewer deaths, and longer life with HIV

human immunodeficiency virus (HIV)

retrovirus (RNA virus)

targets CD4+ t lymphocytes

progressive immune suppression, causes loss of cell-mediated immunity leading to opportunistic infections and cancers

chronic, treatable infection

HIV v AIDS

HIV is a virus

AIDS is an advanced stage of infection (CD4 < 200 cells/uL or AIDS defining illness)

what are common oral manifestations of HIV?

oral candidiasis (pseudomembranous, erythematous)

oral hairy leukoplakia

kaposi sarcoma

necrotizing ulcerative gingivitis / periodontitis

recurrent apthous ulcers

all result from a weakened immune system

because of this, dentists may be the first to suspect HIV

how is HIV transmitted?

blood, sexual fluids, breast milk

standard precautions protect providers

how is HIV NOT transmitted?

casual contact, saliva, dental care

what happens if you get HIV and remain untreated?

decrease in CD4 t cells leading to AIDS and then opportunistic infections that lead to death

what happens if you are infected with HIV and treated?

viral suppression, CD4 recovery

near normal life expectancy, managed as a chronic disease

antiretroviral therapy for HIV

combination required due to high mutation rate

suppresses virus but does not cure- viral load can become undetectable

decreases disease progression and transmission

binding/attachment of HIV

uses CD4 + CCR5 to enter cells

*CCR5 antagonists, post-attachment inhibitors target this step

fusion of HIV

virus enters the cell

*fusion inhibitors target this step

reverse transcription of HIV

RNA to DNA

*NRTIs and NNRTIs target this step

integration of HIV

viral DNA inserted into host genome

*integrase inhibitors target this step

replication of HIV

host makes viral RNA and proteins

no drug targets for this step

assembly and maturation (budding) of HIV

immature viruses are released and become infectious

*protease inhibitors target this step

nucleoside reverse transcription inhibitors (NRTIs)

backbone treatment

tenofovir (TAF, TDF)

emtricitabine / lamivudine

integrase strand transfer inhibitors (INSTIs)

first line anchor

dolutegravir, bictegravir

how are most HIV patients treated?

2 NRTIs + 1 INSTI

combination therapy is required because of high mutation rate

what are the other classes of HIV treatment?

mainly block entry, boost levels, or treat resistant disease

NNRTIs (rilpivirine), protease inhibitors (PIs) (darnunavir)

what is the mechanism of action of nucleoside reverse transcriptase inhibitors (NRTIs)?

nucleos(t)ide analogs

inhibit reverse transcriptase

incorporated into viral DNA which terminates the chain and stops viral DNA synthesis

tenofovir (TAF, TDF), emtricitabine

key NRTIs

what is the dental relevance of NRTIs?

generally well tolerated, minimal drug interactions, no major issues for routine dental care

tldr NRTIs

backbone + chain termination

what is the mechanism of action of NNRTIs?

bind reverse transcriptase (allosteric site)

inhibit enzyme activity

no chain termination (not incorporateed into DNA)