Introduction to Antivirals Flashcards
1
Q
Antivirals
A
- Antiviral agents are inhibitors of viral replication
- Since viral replication is associated with metabolism of the host cells, it is very difficult to develop antivirals that only attack the virus but not the host cell
- oxicities and Resistance
2
Q
Potential Sites for Antivirals
A
- Viral attachment, penetration and uncoating
- Reverse Transcription (retroviruses)
- Viral replication and integration
- Transcription and Translation
- Viral assembly
3
Q
Inhibitors of Viral Attachment
A
- Viral specific spikes interact with a specific receptor on the host cell
- This interaction could be blocked by neutralizing antibodies or other inhibitors
4
Q
Inhibitors of Viral Attachment - HIV
A
•Maraviroc
-HIV-1 coreceptor CCR5
•Enfuvirtide
-HIV-1 gp41
5
Q
Inhibitors of Cell Penetration and Uncoating
A
- Two related synthetic amines, Amantadine and Rimantadine
- Prevent uncoating or RNA transcription, if used early in infection
- Low doses may also inhibit viral assembly
- Both the agents are taken orally and have low toxicities
- Active against Influenza A but not B
- Influenza A virus became resistant to both the agents during treatment, Not used anymore
Prophylaxis: 70% effective if given daily during influenza outbreaks
Mechanism: They target the M2 (matrix) protein
Toxicity: CNS complaints, minor nervousness and light-headedness
6
Q
Inhibitors of Cell Penetration and Uncoating Resistance
A
•Resistance requires only a single amino acid change in transmembrane protein
7
Q
Inhibitors of Viral Release - Neuraminidase Inhibitors: Oseltamivir
A
- Oseltamivir (Tamiflu) selectively inhibits the neuraminidase of influenza viruses - Competitive inhibitor towards sialic acid
- Orally administered
- Reduce influenza symptoms and shorten the course of illness by 1 to 1.5 days
- Active against both influenza A and B
- Recommended above 2 weeks of age and above
- Common adversity: nausea, vomiting, diarrhea, abdominal pain
- Rare adverse reactions: hepatitis, elevated liver enzymes, rash, allergy, anaphylaxis
8
Q
Inhibitors of Viral Release - Neuraminidase Inhibitors: Zanamivir
A
selectively inhibits the neuraminidase of influenza viruses - Competitive inhibitor towards sialic acid
- Orally administered
- Reduce influenza symptoms and shorten the course of illness by 1 to 1.5 days
- Active against both influenza A and B
- given as inhalation powder for oral inhalation, 7 years of age and above
- Common adversity: nausea, vomiting, diarrhea, abdominal pain
- Rare adverse reactions: hepatitis elevated liver enzymes, rash, allergy, anaphylaxis
9
Q
Inhibitors of Nucleic Acid Synthesis
A
- Most antivirals are nucleoside analogs that interfere with viral DNA and RNA syntheses
- Serve as chain terminators after incorporation into the nucleic acids
- Most specific agents work on virus specific nucleic acid polymerases or transcriptases
10
Q
Inhibitors of Nucleic Acid Synthesis: Zidovudine (ZDV) or AZT
A
11
Q
Inhibitors of Nucleic Acid Synthesis: Adenine Arabinoside (Vidarabine)
A
- Purine, inhibits DNA polymerase
- Phosphorylated to its active form intracellularly, 15 to 30 times more
- Susceptible to herpes DNA polymerases than cellular DNA polymerases
- Less toxic than others
- Intravenous administration reduces the mortality of herpes encephalitis
- Useful in the treatment of neonatal herpes infection and herpes zoster in immunocompromised patients
- Used in the treatment of herpes infection of eye
12
Q
Inhibitors of Nucleic Acid Synthesis: Acyclovir
A
- Acycloguanosine
- Very active against replicating herpes simplex virus (HSV)
- Phosphorylates to monophosphate form by virus specific thymidine kinase limiting the presence of the derivative to virus infected cells
- Further phosphorylates to triphosphate form by cellular kinase to inhibit viral DNA polymerase 100 fold greater than cellular DNA polymerase
- It causes termination of herpes DNA elongation
- Little toxicity for host cells
13
Q
Acyclovir and CMV
A
•CMV is resistant to acyclovir because it kinase is unable to phosphorylate acyclovir
14
Q
Acyclovir and VZV and EBV
A
•Less effective against Varicella-Zoster Virus (VZV) and Epstein-Barr virus (EBV)
15
Q
Acyclovir Preparations
A
- Available in topical, oral, and intravenous preparation
- Oral therapy is effective in primary oral and genital herpes simplex infection
- Prophylactic use is helpful in frequent recurrences of herpes
- Intravenous is used to manage severe genital herpes and VZV in immunocompromised and burn patients
16
Q
Acyclovir Resistance
A
- Resistant mutants of HSV and VZV emerge after long term administration due to development of thymidine kinase deficient mutants and alteration in viral DNA polymerase
- Resistant mutants are sensitive to foscarnet and vidarbine because they do not require viral thymidine kinase for activation
17
Q
Acyclovir Prodrugs
A
•Valacyclovir, Famciclovir and Penciclovir are prodrugs of acyclovir
18
Q
Acyclovir Side Effects
A
•Obstructive crystalline nephropathy, acute renal failure if not adequately hydrated
19
Q
Inhibitors of Nucleic Acid Synthesis: Ganciclovir
A
- An acyclovir (nucleoside) analog
- Because it can be phosphorylated by cellular kinase, it inhibits growth of herpesviruses, including CMV and host cells
- Better phosphorylated in CMV infected cells
- CMV UL97 monophosphates it and cellular kinase converts into di- and tri- phosphorylates
- Inhibits viral DNA polymerase function by terminating elongating DNA chain
- Used to treat CMV infection in AIDS patients and CMV retinitis
- Relapses are common when the drug is stopped
- Resistant mutants develop against ganciclovir
- Possesses significant toxicity for uninfected host cells such as, neutropenia, suppressing spermatogenesis, bone marrow precursors and gut mucosal cells
20
Q
Inhibitors of Nucleic Acid Synthesis: Foscarnet
A
- Trisodium phosphonoformate, a pyrophosphate analog
- Directly inhibits DNA polymerase of all herpes viruses, RNA polymerase of influenza viruses and reverse transcriptase of retroviruses
- Does not require activation by viral specific thymidine kinase and thus is highly active against CMV and acyclovir resistant herpes simplex
- It is nephrotoxic and must be administered by continuous intravenous infusion
- Side effects: nephrotoxic, electrolyte abnormalities (hypo or hyper Ca++, PO4-, hypo K+, hyop Mg++.
21
Q
Inhibitors of Nucleic Acid Synthesis: Ribavarin
A
- Synthetic triazole nucleoside, guanosine analog
- Mechanism is unclear but it inhibits the synthesis of guanosine 5’-phosphate required for synthesis of viral nucleic acid
- It is phosphorylated to mono-, di- and triphosphate forms by cellular kinases
- Useful as aerosol in prevention and treatment of some respiratory viral infections (Influenza A and B and RSV)
- Oral and intravenous administration successful in arenavirus infection (Lassa fever)
- Active against hepatitis C virus when combined with interferon alpha
- Side effects: hemolytic anemia, fatigue, severe teratogen (an agent that disturbs embryonic development)
22
Q
Inhibitors of HIV Infection
A
I. HIV Entry Inhibitors
II. Nucleoside Reverse Transcriptase Inhibitors (NRTI)
III. Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI)
IV. HIV Integrase Inhibitors
V. HIV Protease Inhibitor (PI)
23
Q
Inhibitors of HIV Infection: HIV Entry Inhibitors
A
•CCR5 (HIV coreceptor) inhibitor, Maraviroc
- Should be used in combination therapy
- Side effects: cough, fever, dizziness, headache, low blood pressure, nausea, bladder irritation and possible liver problems and cardiac events
•HIV Gp41 Fusion Inhibitor, Enfuvirtide (Fuzeon)
- Inhibits HIV gp41 binding to T cells
- It’s a peptide so it requires injections
- Should be used in combination therapy
24
Q
Inhibitors of HIV Infection: NRTIs
A
- Zidovudine (ZDV or AZT)
- Didanosine (ddI)
- Zalcitabine (ddC)
- Emtricitabine (FTC)
- Stavudine: D4T
- Lamivudine: 3TC
- Tenofovir DF (TDF) or alafenamide (TAF)
- Abacavir (ABC)
25
Inhibitors of HIV Infection: NRTIs - ZDV, AZT
* Zidovudine (ZDV) or Azidothymidine (AZT), a thymidine analog
* Inhibits HIV replication
* Phosphorylates in vivo to 5’-triphosphate form by cellular enzymes
* Inhibits reverse transcriptase by terminating viral DNA elongation
* Monotherapy with AZT in no longer effective
* AZT can be used in combination with other inhibitors of HIV replication
* HIV becomes resistant to AZT after prolonged treatment due to a mutation in the reverse transcriptase
* Significant toxicity for bone marrow and produces severe anemia in 80% of patients
* Useful in reducing the risk of HIV vertical transmission when given during pregnancy
26
Inhibitors of HIV Infection: NRTIs - Didanosine (ddI) & Zalcitabine (ddC)
* Inhibit HIV replication by blocking reverse transcription
* Phosphorylated to active triphosphate form like AZT by cellular enzymes
* Serious side effects include peripheral neuropathy and pancreatitis
* ddI is approved for advanced HIV infection after AZT resistance
* ddC is approved in combination with AZT for adults with advanced HIV infection
27
Inhibitors of HIV Infection: NRTIs - Stavudine (D4T)
* A nucleoside analog that inhibits HIV replication
* D4T is phosphorylated by cellular enzymes to active triphosphate
* Terminates viral nucleic acid synthesis
* D4T is will absorbed and has high bioavailability
* Adverse side effects include headache, nausea and vomiting, confusion, elevated serum transaminase and creatine kinase and peripheral neuropathy
28
Inhibitors of HIV Infection: NRTIs - Lamivudine (3TC)
* A reverse transcriptase inhibitor, comparatively safe and usually well-tolerated
* Phosphorylated by cellular kinases
* Used in combination with AZT or other inhibitors
* 3TC and AZT have unique interactions; 3TC suppresses the development and persistence of AZT resistance mutants
* Useful in treating hepatitis B when combined with interferon alpha
29
Inhibitors of HIV Infection: NNRTIs
* Non-nucleoside analogs inhibit HIV replication
* Nevirapine (NVP), Delavirdine (DLV), Efavirenz (EFV) and Rilpivirine (RPV) NNTRIs
* These compounds do not require phosphorylation and bind to reverse transcriptase
* Active against both AZT-sensitive and AZT-resistant isolates
* Less toxic because they do not inhibit host DNA polymerase
* Drug resistance readily emerges
* Useful when combined with other antivirals
* Side effects: Rash & hepatotoxicity, Vivid dreams and CNS symptoms with EFV; DLV is contraindicated in pregnancy
30
Inhibitors of HIV Infection: HIV Integrase Inhibitor
* Raltegravir, Elvitegravir, Dolutegravir
* Inhibits HIV integrase enzyme that helps integrate HIV genome into host chromosome
* Inhibits DNA strand transfer, no viral mRNA transcription
* Given to patients with HAART resistance
* Should not be used as immunotherapy
* Used in combination therapy for post exposure prophylaxis
* Hepatic metabolism
* Toxicity: minimal, increase in creatine kinase
31
Inhibitors of HIV Infection: HIV Protease Inhibitors
* (Atazanavir, Darunavir, Fosamprenavir, Indinavir, Lipinavir, Nelfinavir, Ritonavir, Saquinavir)
* These agents are used in combination with other class of inhibitors because monotherapy results in rapid drug resistance.
* Protease inhibitors inhibit the HIV protease enzyme that is required to process HIV gag precursors to mature gag (capsid, matrix and nucleocapsid) and HIV Pol to protease, reverse transcriptase and integrase proteins and thus inhibits viral assembly and release or virion maturation.
* Side effects: Hepatotoxic, GI intolerance (nausea, diarrhea), hyperglycemia, lipodystrophy (Crushing –like syndrome), nephropathy, hematuria (indinavir), Contraindicated with Rifampin (anti-TB drug).
32
Inhibitors of HCV Infection: Protease Inhibitor
* Telaprevir (Incivek), Boceprevir (Victrelis) and Simiprivir (Olysio) are approved by FDA
* Target: HCV protease enzyme (NS3-4A gene products of HCV)
* Mechanism: Competitive inhibitor; competes with the substrate (NS5A/5B gene products of HCV) and targets the substrate binding site
* Resistance: HCV quickly becomes resistant to either drug used alone, combination therapy with interferon and ribavirin controls HCV infection.
* Side effects: anemia, rash, nausea, diarrhea, headache, rectal irritation & pain.
33
Inhibitors of HCV Infection: Polymerase Inhibitor
* Nucleotide analog, Sovaldi (Sofosbuvir), inhibits HCV polymerase
* Sovaldi works better for HCV genotypes 2 and 3 without interferon but should be taken with ribavirin
* For HCV genotypes 1 and 4, interferon should be used with Sovaldi
* Side effects: fatigue, headache, nausea
* Non-nucleoside HCV polymerase inhibitor:
- Dasabuvir
- Side effects are nausea, itching, and insomnia.
34
Inhibitors of HCV Infection: NS5A Inhibitors
•Daclatasvir, elbasvir, ledipasvir, ombitasvir, and velpatasvir
Mechanism: Inhibit HCV NS5A (phosphoprotein) function
•Side effects: headache, feeling tired, and nausea
35
Inhibitors of HCV Infection: Nucleotide Inhibitors
* (Cidofovir) Cidofovir is a nucleotide analog that does not require phosphorylation and inhibits viral DNA polymerase.
* It is used to treat CMV retinitis in immunocompromised patient and acyclovir-resistant HSV.
* It has a long half-life.
* Side effects: nephrotoxicity (use IV fluid)
36
Inhibitors of Viral Assembly and Release
•No specific antivirals. However, methisazone acts on poxvirus infection by blocking late viral protein synthesis.
37
Interferons
* Are host proteins that provide first line of defense against viral infections
* Recombinant interferons are commonly used
* Interferon-alpha has shown definite role in herpes zoster and CMV infections
* Proved beneficial in the treatment of chronic hepatitis B and hepatitis C liver infection
* Active against HIV in vitro and synergistic with AZT
* Some toxicity because of effect on host cell protein synthesis •In the presence of interferon, the synthesis of two cellular enzymes is induced:
1. The first is protein kinase that phosphorylates and thereby inactivates one of the subunits of an initiation factor necessary for protein synthesis
2. The second is 2’, 5’ -oligo synthetase that activates a constitutive ribonuclease that degrades mRNA and the action of both enzymes requires double stranded RNA and prevents adverse effect on uninfected cells
* Viral infection of a cell that has been exposed to interferon results in general inhibition of protein synthesis, leading to cell death and no virus production
* Side effects: flu-like symptoms, depression, neutropenia, myopathy
38
Gene Therapy Approach
* Fomivirsen is an antisense synthetic oligonucleotide complementary to CMV mRNA inhibits CMV infection
* Antisense HIV tat and rev mRNAs have been developed
* Trans-dominant tat and rev proteins have been developed
* Several other genetic approaches are underway
39
Antiviral Resistance
•Common mechanisms of resistance to nucleoside analogs
- Rate of viral replication
- Selective pressure of the drug
- Rate of viral mutations
- Rate of mutation in differing viral genes
•Methods to detect resistance
- Genotypic
- Phenotypic
