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TARGETS OF ANTI-VIRAL AGENTS

© Guibelondo, Dex Marco Tiu 6

ANTI-VIRAL AGENTS

Antiherpetic Agents

1. DNA Synthesis/ Polymerase Inhibitors

a. Thymidine Kinase

i. Purine Analog

□ guanine:

a) Aciclovir

b) Valaciclovir

c) Ganciclovir

d) Valganciclovir

e) Penciclovir

f) Famciclovir

□ adenine:

a) Vidarabine

ii. Pyrimidine Analog

□ uridine:

a) Idoxuridine

b) Trifluridine (aka Trifluoropyrimidine)

c) Edoxudine

□ thymine:

a) Brivudine

b) Sorivudine

□ cytosine:

a) Cytarabine

b. Not Thymidine Kinase activated

i. Foscarnet

2. Fusion Inhibitor

a. Docosanol (aka Behenyl alcohol)

3. Adamantane Derivative/ Matrix 2(M2) Proton Channel Inhibitor

a. Tromantadine

AntiVZV

a) DNA Synthesis/Polymerase Inhibitors

a. Thymidine Kinase activated

i. Purine Analog

□ guanine:

a) Aciclovir – for chickenpox

b) Valaciclovir – for shingles

c) Famciclovir

□ adenine:

a) Vidarabine

ii. Pyrimidine Analog

□ cytosine: Cytarabine

b) Antibodies/ Immune Globulin

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a. VZV Immune Globulin

c) VZV prophylaxis/Vaccines

a. Varicella vaccine - chickenpox vaccine

b. Zoster vaccine - a larger-than-normal dose of the vaccine used against

chickenpox; used in older adults to reduce the risk of shingles (herpes zoster) and

postherpetic neuralgia

d) Investigational AntiVZV

a. Valomaciclovir - viral DNA polymerase inhibitor; under clinical evaluation for

treatment of acute zoster and acute EBV infection (infectious mononucleosis)

AntiCMV

1. DNA Synthesis/ Polymerase Inhibitors

a. Thymidine Kinase activated

i. Purine Analog

□ guanine:

a) Ganciclovir

b) Valganciclovir

b. Not Thymidine Kinase activated

i. Foscarnet (aka Phosphonoformic acid)

c. Others

i. Cidofovir

ii. Brincidofovir (experimental prodrug of cidofovir)

2. Early Protein Synthesis Inhibitor

a. Fomivirsen - an antisense oligonucleotide antiviral; CMV treatment in

immunocompromised patients including those with AIDS

Antiretrovirals for HIV

1. N(A)RTIs

a. Abacavir - guanosine analog

b. Didanosine (ddI) - adenosine analog

c. Emtricitabine (FTC) - cytidine analog

d. Lamivudine (3TC) - cytidine analog

e. Stavudine (d4T) - thymidine analog

f. Zalcitabine (ddC) - cytidine analog

g. Zidovudine (ZDV, azidothymidine, AZT) - thymidine analog

2. Nt(A)RTIs

a. Tenofovir disoproxil fumarate (TDF) - adenosine analog

b. Tenofovir alafenamide fumarate (TAF)

3. NN(A)RTIs

a. 1st Generation

i. Delavirdine (DLV)

ii. Nevirapine (NVP)

iii. Efavirenz (EFV)

b. 2nd Generation (diarylpyrimidines)

i. Etravirine (ETR)

ii. Rilpivirine (RPV)

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iii. Doravirine (under development)

4. PIs

a. 1st Generation

i. Amprenavir (APV)

ii. Fosamprenavir (FPV)

iii. Indinavir (IDV)

iv. Lopinavir (LPV)

v. Nelfinavir (NFV)

vi. Ritonavir (RTV)

vii. Saquinavir (SQV)

b. 2nd Generation

i. Atazanavir (ATV)

ii. Darunavir (DRV)

iii. Tipranavir (TPV)

5. Entry/ Fusion Inhibitor

a. GP41 glycoprotein inhibitor

i. Enfuvirtide

b. CCR5 inhibitor

i. Maraviroc

6. INSTIs

a. Dolutegravir (DTG)

b. Elvitegravir (EVG)

c. Raltegravir (RAL)

d. Globoidnan A – a lignan from Eucalyptus globoidea; investigational

7. Pharmacokinetic Boosters

a. Ritonavir – w/ weak PI antiretroviral activity; enzyme inhibitor

b. Cobicistat – purely an enzyme inhibitor; notably used with elvitegravir

8. Ribavirin (aka Tribavirin)

a. MOAs:

i. nucleoside inhibitor (guanosine analog) that stops viral RNA synthesis and

viral mRNA capping

ii. a prodrug which when metabolized resembles purine RNA nucleotides,

interfering RNA metabolism

iii. R-5'-MP inhibits cellular IMP dehydrogenase, depleting intracellular GTP

pools

9. Investigational Antiretrovirals

a. Uncoating Inhibitors

i. TRIM5alpha gene

b. Transcription Inhibitors

i. Tat Antagonists

c. Translation Inhibitors

i. Trichosanthin

AntiHBV

1. N(A)RTIs

a. Entecavir (ETV) - guanosine nucleoside analog

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b. Lamivudine (3TC) - cytidine nuceloside analog

c. Telbivudine - thymidine nucleoside analog

d. Clebivudine - thymidine nucleoside analog

2. Nt(A)RTIs

a. Adefovir dipivoxil (ADV) - adenine nucleotide analog

b. Tenofovir disoproxil fumarate (TDF) - adenosine nucleotide analog

c. Tenofovir alafenamide fumarate (TAF)

AntiHCV

1. NS3/4A Serine Protease Inhibitor (-previr)

a. Asunaprevir (currently in Phase III)

b. Boceprevir

c. Grazoprevir

d. Faldaprevir (withdrawn from the market)

e. Paritaprevir (an acylsulfonamide)

f. Simeprevir

g. Telaprevir

2. NS5A Inhibitors (-asvir)

a. Daclatasvir

b. Elbasvir

c. Ledipasvir

d. Odalasvir (Phase III)

e. Ombitasvir

f. Ravidasvir (Phase III)

g. Samatasvir (Phase III)

h. Velpatasvir

3. NS5B RNA Polymerase Inhibitors

a. Beclabuvir (Phase III)

b. Dasabuvir

c. Deleobuvir (Never to Phase III)

d. Filibuvir (Never to Phase III)

e. Setrobuvir (Never to Phase III)

f. Sofosbuvir

g. Radalbuvir (Phase III)

4. Ribavirin (aka Tribavirin) – see Antiretrovirals for all observed MOAs

5. Investigational AntiHCVs

a. miR122 Inhibitor

i. Mivavirsen (an antisense oligonucleotide)

b. p7 Inhibitors

c. NS4B Inbibitors

d. Cyclophilin Inhibitors

Anti-Influenza

1. NIs/Sialic acid analogs/ Progeny Release Inhibitors

a. Oseltamivir – for Influenza A and B

b. Zanamivir – for Influenza A and B

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2. Adamantane Derivatives/ Matrix 2(M2) Proton Channel Inhibitors

a. Adapromine (1-(Adamantan-1-yl)propan-1-amine) - alkyl analog of rimantadine;

active vs Influenza A and B

b. Amantadine (1-aminoadamantane hydrochloride) - for Influenza A only

c. Rimantadine (1-(1-aminoethyl)adamantane) - for Influenza A only Anti-Influenza

3. Fusion/Entry Inhibitor

a. Umifenovir

i. chemically features an indole core, functionalized at all but one positions

with different substituents

ii. Other MOAs: (1) stimulation of humoral immune response, (2) induction

of interferon production, (3) stimulation of phagocytic function of

macrophages

4. Investigational Anti-Influenza

a. Peramivir - NI good for Influenza A and B (a cyclopentane analog)

b. Laninamivir octanoate - long-acting NI for Oseltamivir-resistant virus

c. DAS181 - host-directed antiviral agent that removes the virus receptor, sialic acid,

from adjacent glycan structures

Other Antiviral Agents

1. Interferons:

a. MOAs: inhibition of (1) viral penetration or uncoating, (2) mRNA synthesis, (3)

viral protein translation, (4) viral protein assembly and release

b. Indications: Venereal warts (condyloma acuminatum), chronic hepatitis B and C,

Kaposi's sarcoma, MS

c. PEG-Interferon - 40 kDa; has the advantage of sustained delivery and reduced

clearance of interferon

d. alpha and beta interferons - produced by all cells in response to viral infections;

effective against HBV, HCV, and HPV

e. gamma interferon - produced only by T lymphocyte and NK cells in response to

cytokines; has immune regulating effects; less antiviral activity as compared to

alpha and beta interferons

2. Ribavirin (aka Tribavirin) - also for RSV and Influenza A & B; see Antiretrovirals for all

observed MOAs

3. Palivizumab - Humanized IgG1 monoclonal antibody directed against an epitope in the A

antigen on the F surface protein of RSV

4. RNA interference therapeutic ALN-RSV01 - RSV treatment or prophylaxis

5. Benzodiazepine RSV604 - RSV treatment or prophylaxis

6. Immune Response Modifiers [Toll-Like Receptor 7 (TLR7) Activators]:

a. Imiquimod - topical treatment of external genital and perianal warts (i.e.,

condyloma acuminatum); Cells activated via TLR7 secrete cytokines (primarily

IFN-a), IL-6, and TNF-a

b. Resiquimod - antiviral and antitumor; topical gel for HSV and cutaneous T cell

lymphoma; adjuvant to increase vaccine effectiveness; several MOAs: (1) TLR7

activation, (2) TLR8 agonism, (3) upregulation of opioid growth factor receptor

(u-opioid receptor; regulates tissue growth, involved in embryonic development,

wound repair, and certain forms of cancer)

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c. Gardiquimod - structurally extremely similar to resiquimod differing only by an

oxygen for nitrogen switch