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PMCOL 344 > Lecture 6/7: Antivirals > Flashcards

Lecture 6/7: Antivirals Flashcards

1
Q

Viruses-intracellular parasites

A 
Uncoating
Replication
Transcription
Translation
Assembly
Maturation and release
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2
Q

Targeting viruses

A

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

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3
Q

Influenza virus infections

A 
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
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4
Q

Amantadine and Rimantadine

A

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

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5
Q

Neuraminidase

A

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

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6
Q

Neuraminidase Inhibitors

A

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

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7
Q

Oseltamivir-tamiflu

A

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

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8
Q

Zanamivir(relenza)

A

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

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9
Q

Herpes Virus

A

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

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10
Q

Acyclovir:

A

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

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11
Q

Ganciclovir

A

CMV retinitis.
Acyclic nucleoside analog
Potent inhibitor of HSV and CMV replication
Bone marrow toxicity dose limiting

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12
Q

Phosphonoformic Acid(foscarnet)

A

Pyrophosphate analog
Blockade of the PPi binding site of viral DNA polymerase
CMV retinitis
HSV, VZV infections (acyclovir resistant)
Renal toxicity dose limiting

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13
Q

Ribavirin

A

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)

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14
Q

HIV

A

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

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15
Q

Steps to HIV infections

A

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

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16
Q

Antiretroviral Drugs

A

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

17
Q

Highly active antiretroviral therapy(HAART)

A 
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
18
Q

Nucleoside reverse transcriptase inhibitor(NARTI)

A

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

19
Q

Non-nucleoside Reverse Transcriptase inhibitors(NNRTI)

A

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

20
Q

Protease inhibitors are peptidomimetics

A

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

21
Q

Fusion or Entry Inhibitors

A

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

22
Q

Maraviroc

A

binds to the CCR5 on cell-prevent interaction with gp120

Negative allosteric modulator of the CCR5 receptor

23
Q

Enfuvirtide

A

binds to gp41 and interferes with its ability to merge the two membranes
Expensive and inconvenient dosing regime

24
Q

Integrase Inhibitors

A

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

25
Q

Hepatitis B Virus(HBV) and Hepatitis C Virus(HCV) Infections

A

At least 5 forms of viral hepatitis caused 5 different viral strains-hepatotropic viruses
HBV and HCV cause acute and chronic infections
Hep A usually self-resolving and does not result in chronic infections

26
Q

Hepatitis B Virus(HBV)

A

Double-stranded DNA virus
DNA–(Host enzymes)–>4 mRNA–(viral reverse transcriptase)–> DNA
Transmission: sexual intercourse, parenteral(drug needle)
Chronic HBV: linked to development of heptacellular carcinoma and cirrhosis
Effective vaccine
None of the available drugs can clear the infection, but they can stop the virus from replicaitng, thus minimizing liver damage

27
Q

Hepatitis C Virus(HCV)

A

(C)single-stranded RNA virus
Transmission- parenteral(needles)
Symptoms mild at firts
Chronic disease-linked to development of hepatocellular carcinoma and cirrhosis
NO VACCINE YET…
HCV characterized by extraordinary genetic variability resulting from lack of proofreading activity(like HIV) of the NS5B RNA-dependent polymerase-many HCV variants in one infected individual

28
Q

Interferon Alpha

A

Protein
Produced naturally by monocytes and B-cells
Available as recombinant preparation
PEGylated Interferon alpha(long acting) is now used
Mechanism: induction of cellular enzymes that inhibit synthesis of viral mRNA and proteins
Indication: chronic HBC and HCV, also useful for chronic HCV and HIV co-infection
Toxicity: acute flu-like syndrome, during chronic therapy-Myelosuppression and neurotoxicity

29
Q

Interferon alpha + ribavirin for chronic hepatitis C

A

Sustained response in 40% HCV patients, reduction in liver damage(ribavirin), loss of detectable HCV RNA(interferon)

30
Q

3TC(Lamivudine)

A

Second-line treatment of HBV infection
Cytidine analogue
Viral reverse transcriptase inhibitor
Reduce risk of HBV re-infection in liver transplant
Hepatitis flare after discontinuation of 3TC
Well-tolerated

31
Q

Protease inhibitor

A

New: telaprevir-inhibits the NS3-NS4A viral protease and inhibits formation of critical proteins
Inhibits hep C viral enzymes NS3.4A serine protease
Inhibition NS3/4A/5A protease prevents viral replication and subsequently reduces HCV RNA levels
Examples: boceprevir, telaprevir, simeprevir, ledipasvir, declatasvir
HCV genotype 1 and 4 only-2,3 and 5 don’t work
Combo therapy with interferon alpha and ribavirin
Resistance is common

32
Q

Sofosbuvir

A

HCV RNA polymerase inhibitor
Prodrug-metabolized to GS-461203
Mechanism: Inhibits the HCV NS5B protein(viral RNA polymerase)-RNA chain terminator
Used in combo with ribavirin, interferon alpha and protease inhibitors( interaction Pgp pump)
Genotype 1,4,5, and 6 HCV in combo with ledipasvir
Genotype 2 and 3 in combo with ribavirin or interferon
Less prone to development of resistance
Now part of most first-line treatments for HCV

33
Q

Steps of COVID lifecycle

A 
Attachment: S1 domain of the spike proteins with cognate receptor.  This drives conformational change in the S2 subunit in S, promoting the fusion of viral and cell PM
Entry:RNA enters
Replication
Translation: RNA translated to make replicase-polymerase
Transcription
Translation
Assembly
Release

PMCOL 344 (8 decks)

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