Anti-viralAgents →↑↓ Flashcards
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**Life cycle of Virus
Viruses Hijack Our Cells
Viruses are intracellular parasites
Live and replicate inside other living cells
Depends on the synthetic processes of the host cells
Different virus have different host cells
Influenza Viruses
HSV
HIV virus
Influenza virus
Hemagglutinin HA
Neuraminidase NA
HA promotes binding and entry
NA allows budding and release
HSV
Glycoprotein gB gC
Cell surface proteoglycans (Heparan sulfate)
Glycoproteins gD of HSV bind to TNF NGF family protein receptor
MEmbrane fusion and viral penetration
HIV
CD4 receptor binding
co-receptor binding
Conformational change in gp120 Gp41 can initiate fusion
Replication of genetic materials& integration to the host genome
DNAvirus→enter cell as viral RNA → Viral DNA → integrated viral DNA between target site duplication
Budding
Release
Budding out (host cells intact
lysis of host cell
Types of Herpes Virus Infections-life long infection
Cytomegalovirus Disease and Retinitis
caused by
cytomegalovirus
Genital herpes infection
caused by herpes simplex virus
Herpes zoster
caused by varicella-zoster virus
Herpes zoster infection
caused by varicella-zoster virus
Highlycontagious
Most children are infected by early age
First exposure: Chickenpox
Latent infections: nerve cells(dorsal ganglion)
Reactivation: Shingles
Vaccine is available (MMRV)
Drugs for Herpes Virus Infection (Nucleoside analogs)
Inhibiting DNA/RNA Synthesis
Mechanism, Route of Acyclovir
is a guanine analog
Mechanism of actions:
- Competitive substrate for DNA polymerase.
- Leads to chain termination
Acyclovir has to be activated by thymidine kinase (only in infected cell) to form acyclovir triphosphate.
Intravenous (IV) preparation
Used for treatment of serious infections.
Oral preparation –Effective in treating primary infections. Less effective in treating recurrences.
Topical preparation –Keep an outbreak contained to a small area. (Treatment for cold sore on mouth)
Long term prophylaxis –Decreases the frequency of recurrences of genital herpes. (can be re-activated by strong sunlight, stress….etc.)
Toxicity: (oral) GI distress, headache.
Acyclovir and its derivatives
Valacyclovir Famciclovir Canciclovir Valganiclovir Trifluridine Idoxuridine Vidarabine
Drugs for Herpes virus infections (Inhibiting viral entry)
Docosanol
Prevents vira lentry, inhibits fusion between HSV envelop and plasma membranes.
Structure and classification Influenza (Flu)
Caused by enveloped RNA viruses.
- Influenza A
- Influenza B
- Influenza C
Classified based on NP, M1 and M2 proteins
Nomenclature of Influenza A
Divided into 18 H (H1-H18) and 11 N (N1-N11) subtypes.
Potentially 198 different subtypes of influenza A viruses.
Only viruses of the H1N1, H1N2, H3N2, H5N1, H7N3, H7N7, H9N2 have expanded their host to humans.
Reason Emergence of new strains
Natural Reservoir –large variety of species (chickens, birds, ducks, pigs and humans).
Animal to human transmission.
Re-assortment of the segmented genome of 2 parent viruses.
Mutation occurs at high rate (especially on the surface glycoproteins).
New variant is able to escape the host defense (vaccinated or not vaccinated).
Influenza B and C
Influenza B
Not divided into subtypes.
Type B flu is found only in humans and seals.
This limited host limits the generation of new strains by re-assortment.
Mutate at a rate 2 to 3 times lower than A viruses.
Do not cause pandemics.
Influenza C
Found in humans
People generally do not become very ill from the influenza type C viruses
Transmission and symptoms of Influenza
Nasal secretions
Aerosols containing the virus
Direct contact with bird droppings
Contact with contaminated surfaces
Usually recover in 2-7 days
Causes serious respiratory illness (hospitalization and death) in weak/frail or elderly people
Flu can be distinguished by a high fever with a sudden onset and extreme fatigue (usually more severe)
Antiviral drugs are effective in treating influenza
Only if given at early stage of infection
Mechanism of Entry of Influenza cells
Hemagglutinin (HA) –involved in the binding of the virus to host cell receptors
Neuraminidase–concerned with release of progeny virions from the cell surface.
Drugs for Influenza Virus Infection (Amantadine / Rimantadine)
Amantadine / Rimantadine
Prevention or treatment of influenza A infection only
Should be given within 48 hrs after contact.
- Block pore formation by M2 proteins of influenza A only
- Prevents H+ions from entering the virus.
- Prevents acidification of the virus core, which is required to active viral RNA transcriptase.
Toxic effects: GI irritation, dizziness, ataxia, slurred speech.
Oseltamivir(Tamiflu) / Zanamivir
Effective for influenza A or B infection
Resistance are increasing
More effective if used within 24 hrs(Five-day therapy)
MoA
- Binds to Influenza neuraminidase
- Prevents the cleavage of sialic acid residues
- Inability to release progeny virions
Prevent the spread of virus after it reproduces !
Peramivir
First FDA-approved IV drug of influenza in Dec 2014
Neuraminidase inhibitor
Effective against both influenza A and B viruses.
Administrated intravenously
Intended to be given in a single dose.
For patients who have difficulty with inhaled or oral medicines.
Common side effects:
Diarrhea, in less than 2% of patients.
Rare side effects:
Stevens-Johnson syndrome
and erythema multiforme
Baloxavir (Xofluza; PA endonuclease inhibitor):
Effective against influenza A & B virus
Administered in a single dose
Significantly shorten the duration of flu symptoms
Inhibits polymerase acidic endonuclease, thus impairs mRNA synthesis and prevents virus to reproduce
Structure and Types and Properties of Human Immunodeficiency Virus (HIV)
Is a retrovirus
HIV-1 (America)
HIV-2 (Africa)
HIV Latency: Many years before causing any symptoms.
- transmit it to others through their blood and bodily fluids
- develop into AIDS
- eventually weakens the immune system, that the patient may die of rare infections that would never be a problem for a healthy person
HIV virus is designed for fast evolution because it makes a lot of mutations when copying its own genome to make new virus particles (No proof read mechanism)
Thus, the viruses in an infected person’s body are constantly changing, which helps HIV become resistant both to the immune system and to the drugs that are used to treat it.
HIV infections must always be treated with a combination of drugs, so that if a virus arises that is resistant to one drug, it is most likely still susceptible to the other drugs in the treatment regimen
Combinations of drugs is the cocktail treatment
Highly active anti-retroviral therapy (HAART)
MoA of HIV Infection
Mostly infectsCD4+cells (alsocalled T-lymphocytes).
Destruction of CD4+cells impairs the immune system resulting in an increase risk of opportunistic infections.
Progression of HIV infection to acquired immunodeficiency syndrome(AIDS) occur in four phases:
Influenza-like symptoms
Virus undergoes rapid replication
Dramatic decline of CD4+ in viral replication
Immune system is damaged Viral production increase.
Drug for Attachment inhibitor of HIV:
Rukobia (Fostemsavir)
Phosphonooxymethylprodrug of temsavir
Temsavir binds and inhibits the activity of gp120, a subunit within the HIV-1 gp160 envelope glycoprotein that facilitates the attachment of HIV-1 to host cell CD4 receptors
Side effect: May induce ALT and AST levels in patients with Hep B or C, Nausea.
Drug of Entry/ Fusion inhibitor of HIV 1
Maraviroc
Attachment of HIV also involves transmembrane chemokine receptor CCR5.
Maraviroc blocks CCR5 and hence reduces viral attachment.
Adverse effects: Cough, diarrhea, muscle, joint pain
Drug of Entry/ Fusion inhibitor 2
Enfuvirtide
A synthetic 36amino-acidpeptide.
Binds to the gp41 subunit of the viral envelope glycoprotein
Prevents conformational changes needed for the fusion of the membranes.
Administrated subcutaneously.
HIV as an RNA virus
Once HIV infected CD4+ lymphocytes, it replicates its genetic materials by converting RNA genome into DNA using its own reverse transcriptase so that its proteins can be expressed by the cell.
Many anti-HIV drugs target this HIV specific reverse transcriptase.
Nucleoside or Nucleotide Reverse Transcriptase Inhibitors (NRTIs)
Inhibiting DNA Synthesis
Structurally similar to natural occurring specific nucleosides/nucleotides
Act as terminators via their insertion into the growing DNA chain.
Lacks a 3’hydroxyl group on the ribose ring, attachment of the next nucleotide is impossible.
Nucleoside analogs of HIV
Zidovudine Abacavir Diadanosine Lamivudine Emtricitabine Stavudine Zalcitabine
Nucleotide analog of HIV
Tenofovir
Newer drug
Used for salvage therapy for multiple drug failures
Non-nucleoside Reverse Transcriptase Inhibitors
Another specific class of reverse transcriptase inhibitors.
They are not competitive substrates of reverse transcriptase.
But directly binds to reverse transcriptase and changes its structure so that the active site is disrupted.
Name of Non-nucleoside Reverse Transcriptase Inhibitors
Efavirenz Nevirapine
Effective in preventing HIV
vertical transmission
Given as single doses to mothers at the onset of labor and to the neonate
MoA of Integrase Inhibitors
Virus must incorporate its genome into the host cell genome so the viral genetic material can be replicated.
The integration is accompanied by an HIV enzyme called integrase.
Raltegravir inhibits integrase
Moa of Protease inhibitors
HIV synthesizes all of its important proteins, including reverse transcriptase, integrase …etc.
As one large polypeptide chain with multiple proteins connected together.
In order for these proteins to work and form a mature viral particle, it must first be cut apart from each other using the HIV protease (also known as aspartate protease).
No new viral particle can be generated
Name of Protease inhibitors (PI)
Lopinavir (The oldest protease inhibitors) Atazanavir Indinavir Saquinavir Ritonavir Nelfinavir Amprenavir Fosamprenavir D arunavir Saquinavir Tipranavir
Ritonavir is administrated concurrently to boost the bioavailiabity of another PI
Drawbacks of proteases inhibitors
Many drug-drug interactions
Disorders in carbohydrate & lipid metabolism
Insulin resistance, hyperglycemia, hyperlipidemia
Buffalo Bumps Gynecomastia
Adverse effects of Protease inhibitors
GI disorders
Hepatoxicity
Increase bleeding risk in hemophiliacs
Kidney stone
Regimen
2NRTIs and a protease inhibitor
2NRTIs and 1NNRTI ( most commonly efavirenz) or
3NRTIs (one should be abacavir
Therapy with a single anti-HIV medication should never be used, except with possible exception of pregnancy to reduce perinatal transmission.
Monoclonal Antibody Ibalizumab for Multidrug-Resistant HIV-1
This is a new class of antiviral medication specifically for adultsliving with HIV who have tried multiple HIV medications and whose HIV has been resistant to current available therapies.
A humanized IgG4 monoclonal antibody
Binds to extracellular domain 2 of the CD4 receptors to prevent post-attachment conformational changes in the CD4-HIV envelope gp-120 complex and block viral entry into the host CD4 cell.
Blocks your body’s HIV infected cells from spreading the virus into those which are uninfected
It is administered by IV every two weeks»_space; combine use with other antiviral agents
Adverse effect of Ibalizumab
No reported drug–drug interactions
Most common adverse effects are diarrhea, dizziness, nausea, and rash.
Names highlighted in summary drugs name
Nucleoside reverse transcriptase inhibitors NRTIs
Zidovudine
Nucleotide reverse transcriptase inhibitors
Tenofovir
Non-nucleoside reverse transcriptase inhibitors
Efavirenz
Names highlighted in summary drugs name
Nucleoside reverse transcriptase inhibitors NRTIs
Zidovudine
Nucleotide reverse transcriptase inhibitors
Tenofovir
Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
Efavirenz
Entry inhbitors
Maraviroc
Integrase inhbitiors
Raltegravir
Attachment inhibitors
Fostemsavir
Protease inhbiitors
Indinavir
Monoclonal Antibody
Ibalizumab
