Lecture 6/7: Antivirals Flashcards
Viruses-intracellular parasites
Uncoating Replication Transcription Translation Assembly Maturation and release
Targeting viruses
Inactivate extracellular virus particles
Prevent viral attachment and/or entry
Prevent replication of the viral genome
Prevent synthesis of specific viral protein(s)
Prevent assembly or release of new infectious virions
Influenza virus infections
Influenza viruses: Respiratory pathogens Cause epidemics of respiratory disease Single-stranded segmented RNA genome High mutation rate 3 types 1. Most cases of epidemic influenza 2. Some epidemic 3. Only mild illness Strains(in Type A or B): glycoprotein differ H(emaggulitin) and N(euraminidase) H1N1, H2N2, H5N1 Typical influenza virus vaccine contain one type A H1N1, one type A H3N2 and either one or two type B strain
Amantadine and Rimantadine
Prophylaxis and treatment of influenza A infection
Mechanism: inhibit pH dependent uncoating of the virus inside cells
Block proton channel M2 in the viral envelope
SFX: CNS sfx at hi dose(less frequent with rimantadine), safety in preggo not established
Resistance: rapid emergence during treatment, two drugs share cross susceptibility. No longer used very much bc wide-spread resistance
Neuraminidase
Viral neuraminidase(sialidase):
Cleaves sialic acid residues from cell membrane receptor
Release virus that is bound to cell membrane through interaction btwn sialic acid and viral envelope
Activity required for release of newly-formed virus from infected cells
Neuraminidase Inhibitors
Mimic N-acetylneuraminic acid(sialic acid)
Selective for viral neuraminidase
Inhibit viral release and spread
Effective against both influenza A and B
Enable more rapid recovery from influenza
Do not cause significant adverse effects
Resistance: to single amino acid substitution in the neuraminidase enzyme
Oseltamivir-tamiflu
Transition-state analogue inhibitor of Neuraminidase-irreversible
Prevent viral particles from being released from infected cell
Co-administration with probenecid(prevent excretion) to maintain peak plasma concentration
SFX: nausea and vomiting
Zanamivir(relenza)
Competitive inhibitor or neuraminidase
Reduce the time to symptom resolution by 1.5 days provided therapy was started within 48hrs of onset of symptoms
Retain activity against Oseltamivir resistant-H5N1 due to difference in how it fits in the binding pocket
SFX: Diarrhea, nausea, sinusitis
Herpes Virus
Herpes simplex virus(HSV), Cytomegalovirus(CMV), Varicella-zoster virus(VZV) and Epstein-Barr Virus(EBV)
Double-strand DNA genome
Establish lifelong, presistent infection in host
Initial infection: in epithelial cells
Latent infection: in neurons(HSV,VZV) or lymphocytes(CMV, EBV)
See pic for 4 types
Acyclovir:
nucleoside analogue, inhibits replication of HSV and VZV
Prodrug, viral thymidine kinase(infected cell)-make acyclovir monophosphate, host enzymes(acyclovir triphosphate)
Inhibits viral DNA polymerase, incorporated as DNA chain terminator
Ganciclovir
CMV retinitis.
Acyclic nucleoside analog
Potent inhibitor of HSV and CMV replication
Bone marrow toxicity dose limiting
Phosphonoformic Acid(foscarnet)
Pyrophosphate analog
Blockade of the PPi binding site of viral DNA polymerase
CMV retinitis
HSV, VZV infections (acyclovir resistant)
Renal toxicity dose limiting
Ribavirin
Purine nucleoside analogue-guanosine analogue
Ribavirin-5’-triphosphate is an RNA mutagen
Ribavirin-5’-monophosphate inhibits IMP dehydrogenase
Slows down DNA/RNA replication and depletion of GTP and dGTP
Used to treat a number of DNA and RNA viruses
Ribavirin is the only known treatment for respiratory syncytial virus infections(RSV)
HIV
Illness is aids, virus is HIV
A retrovirus-single stranded RNA genome and replicates via a DNA intermediate
Primary etiologic agent of acquired immunodeficiency syndrome(AIDS)
Invades and destroys: Helper T lymphocytes (CD4+)
Patients vulnerable to opportunistic infections
Steps to HIV infections
Fusion of the HIV cell to the host cell surface
HIV RNA, reverse transcriptase, integrase, and other viral proteins enter the host cell
Viral DNA is formed by reverse transcription
Viral DNA is transported across the nucleus and integrates into the host DNA
New viral RNA is used as genomic RNA and to make viral proteins
New viral RNA and proteins move to cell surface and a new, immature, HIV virus forms
The virus matures by protease releasing individual HIV proteins
Antiretroviral Drugs
HIV lacks proofreading enzymes to correct errors made when it converts RNA to DNA
Its short life-cycle and high error rate cause the virus to mutate very rapidly=genetic variability-resistance to antiretrovirals
When antiretroviral drugs are used improperly, the multi-drug resistance strain can become the dominant genotype very rapidly
Highly active antiretroviral therapy(HAART)
Strand therapy for HIV involves combination-usually a triple drug cocktail Entry/fusion inhibitors Nucleoside RT inhibitors Non-nucleoside RT inhibitors Integrase inhibitors Protease inhibitors
Nucleoside reverse transcriptase inhibitor(NARTI)
AZT, ddl, ddC, 3TC
Mechanism of action of dideoxynucleosides(missing hydroxyl on ribose ring):
Metabolized by cellular enzymes
5’-triphosphate derivatives are active intermediates
Inhibit reverse transcriptase
Are DNA chain terminators
Toxicities:
AZT- bone marrow suppression
ddL- painful peripheral neuropathy pancreatitis
ddC-peripheral neuropathy
3TC-occasional neutropenia-rapid resistances when 3TC used alone
Non-nucleoside Reverse Transcriptase inhibitors(NNRTI)
Ex. Nevirapine, efavirenz
Active without being metabolized
Bind to an allosteric, non-substrate site of reverse transcriptase
Binding site is distant from that of NARTI’s
Drug interaction by inducing CYP3A4 and CYP2B6
Rapid emergence to resistance when used as single agents
Usually used in combo with nucleoside reverse transcriptase inhibitors and protease inhibitors
Protease inhibitors are peptidomimetics
Ex. saquinavir, indinavir, ritonavir, nelfinavir, amprenavir
HIV encodes an aspartate protease that is essential for viral replication
Protease inhibitors block the activity of this enzyme-blocks viral maturation
Used in combo with nucleoside analogs or non-nucleoside reverse transcriptase inhibitors
Fusion or Entry Inhibitors
Prevent HIV from binding to or entering cells
HIV entry require
Bind HIV to surface protein gp120 to the CD4 receptor
Conformational change in gp120 which both increases affinity for co-receptor and exposes gp41
The binding of gp120 to a co-receptor either CCR5 or CXCR4
The penetration of the cell membrane by gp41 which approximates the membrane of HIV and the T cell and promotes their fusion
The entry of viral core into the cell
Maraviroc
binds to the CCR5 on cell-prevent interaction with gp120
Negative allosteric modulator of the CCR5 receptor
Enfuvirtide
binds to gp41 and interferes with its ability to merge the two membranes
Expensive and inconvenient dosing regime
Integrase Inhibitors
Integrase inhibitors interfere with the integrase enzyme which HIV needs to insert its genetic materials into the DNA of human cells
Raltegravir, used in combo therapy
