unit 09: antivirals Flashcards
wht si a virus
sub-microscopic infectious agent that cannot grow or reproduce outside of a host cell.
They are approximately one hundred times smaller than bacteria.
- simple structure, containing RNA or DNA, protein coat called capsid and some viruses ahve lipid rich envelope
how are viruses classified?
baltimore classification system - thier mechanism of mRNA production
- viruses need to generate mRNA in order to produce proteins and replicate
- virgal genomes can be ss or ds, RNA or DNA
- may or may not use Reverse transcriptase
*ssRNA viruses can either be + sense or - antisense
what are the 7 classifications of viruses?
I: dsDNA viruses (e.g. adenoviruses, herpesviruses)
II: ssDNA viruses (e.g parvoviruses)
III: dsRNA viruses (e.g reoviruses)
IV: (+)ssRNA viruses (e.g coronaviruses like SARS-CoV-2, flaviviruses like West-Nile)
V: (-)ssRNA viruses (e.g influenzaviruses)
VI: ssRNA-RT viruses (e.g retroviruses like HIV)
VII: dsDNA-RT viruses (e.g hepadnaviruses like hepatitis B)
Viral Life cycle
- virus attaches to host cell, mediated by proteins on viral surface that bind specifically to particular component
- Viron undergoes entry by crossing host cell membrane
- virion uncoats losing caspid proteins, nucleic acid becomes available for transcription into mRNAs
- mRNAs transcribed and translated (early protein synthesis)
- Replication of genome followed by late protein synthesis. Viral proteins are synthesized
- Viral proteins assemble with viral genomes within host cell through assembly - many viruses also have mauration after
- final release step by lysis or budding
*antivirals taret one of these steps
what drugs target attachment/are entry inhibitors
Maraviroc
enfuvirtide (T-20)
what drugs are viral ion channel blockers?
amantadine and rimantadine
What drugs are polymerase inhibitors
Acylovir, zidovudine and efavirenz
what drug are integrase inhibitors
raltegravir
what drugs are protease inhibitors?
Saquinavir and ritonavir
what drugs are neuraminidase inhibitors?
Zanamirvir and oseltamivir
what are common viral infectiosn, series/chronic ones latent and cancer viral infections?
common: colf, flu, chicken pox an now COVID-19
serious/chronic: avian flu, ebola, HIV/AIDS and hepatitis
latent: cold sores and singles
cancer ifnections: HPX and EPstein-barr (monomucleosis)
innate vs adaptive immune system
innate: non specific responses to pathogens that activates the adaptive immune response
*invovles macrophages, dendritic cells, neutrophils, eosinophils and basophils/mast cells
adaptive: neutralizing reactiosn that are specific to the offending agent- involve pathogenic recognition
*involves cytotoxic T cells, helper T cells and B cells.
development of cells in immune system
- all hematopoietic cells develop from the pluripotent hematopoietic stem cell -> gives rise to lymphoid stem cell and tri-lineage myeloid stem cell
Lymphoid:
- mature lymphocytes (B and T cells) mediate adaptive
- B cells differentiate into antibody-producing plasma cells, and T cells adopt an activated phenotye when exposure to specific antigen
Myeloid
- megakaryocytes, erythroblasts, and myeloid precursors differentiate itno
- mature neutrophils, eosinophils, basophils, mast cells, monocytes, platelets, and erythrocytes.
- in tissues monocytes differentiate tineo macrophages and mast cells precursors diff into mast cells
what is Oseltamivir
Aka Tamiflu
For prevention and treatment of early infection of influenza A and B *H1N1 is subtype of influenza A SO IT IS RESPONSIVE TO IT
Neuraminidase inhibitor that blocks viral release from host cell
Influenza virus encodes an envelope-bound enzyme neuraminidase, which permits release of the virus
Without this enzyme, the virus would remain tethered and would be unable to spread.
*administed as pro drug and metabolized in liver and GI, excreted in urine
adverse effects of oseltamivir
naesea and GI dsicomfort
reistance to oseltamivir
occurs due to mutations in neuraminidase but the mutant strains are usually less virulent
what is amantadine
also treats influenca
Inhibts viral uncoating by inhibition proton ion channel M2 in the viral envelope of influenza A - inhibits the binding of the virus with endosomes that inhibits uncoating
treatment of early infection by influenza A (not H1N1) and resistance can occur following a mutation in M2
-Distributed throughout body, including CNS and excretedunchanged by kidney
adverse effects of amantadine
GI disturbances, CNS disturbances (nervousness, insomnia, difficulty concentrating) and renal damage in patients w/ renal insufficiency
what causes herpes
herpes simplex = viral disease caused by
herpes simplex virus 1 (HSV-1) and herpes simplex virus 2 (HSV-2). HSV-1 is responsible for most cold sores while HSV-2 infections cause genital herpes
both are extremely contagious. HSV infections cycle between the active phase and remission.
acyclovir
- used to treat herpes by inhibition of viral DNA synthesis
- activation of drug is 3 step mech:
Acyclovir = guanosine analogue, meaning that when phosphorylated, it competes with dGTP during DNA synthesis
- when taken up by infected cells the viral thymidine kinase enzyme catalyzes the phosphorylation of the drug
- phosphorylated acyclovir is then produced only in HSV-infected cells, which interferes with viral DNA synthesis, resulting in DNA chain termination
*oral Iv and topical forms avail
adverse effects of acyclovir
nausea, vomiting, diarrhea, headache and renal damage (especially following high doses or in dehydrated patients
clinicaluse and resistance of acyclovir
treatment of active herpes infection, and resistance can occur if thymidine kinase is altered or deficient.
what is HIV and AIDS
HIV = human immunodeficiency virus -> causes AIDS acquries immune deficiency syndrome
- HIV can be latent for 2-10 years but once aquire AIDS lifespan of untreated is 1-2 years
what type of virus is HIV
retro virus that infects CD+ T cells
The virus attaches where interactions between viral proteins (gp41 and gp120) and host cell CD4 and CCR5 receptors occur
- viral mem fuse w/ host PM allowing HIV genome to enter, uncoat and have genome copied
*DNA is integrated into host cell genome
- gene transcription produced HIV RNA which is translated into proteins from host ribosomes
- proteins assumble into immature virons that bud from host cell membrane then maturations to product fully infective virons
how many drugs to treat HIV
34
what is the first line of treatment
combo of 3 antiviral agents knows as HAART (highly active antiretroviral therapy)
what are the main categoies of antiviral drugs for HIV
- nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) such as zidovudine or azidothymidine (AZT)
- non-nucleoside reverse transcriptase inhibitors (NNRTIs) such as nevirapine
- protease inhibitors (PIs) such as ritonavir.
*HAART often involved two NRTis in combo with an NNRT or PI
what HIV drugs inhibit viral entry
maraviroc
what HIV drug inhibts enzyme integrase
raltegravir
what is zidovudine/AZT
thymidine analogue that is activated or phosphorylated by mammalian kinase.
Like with acyclovir- viral reverse transcriptase is not selective, therefore phosphorylated zidovudine/AZT competes with dTTP during DNA synthesis and results in DNA chain termination.
*well distributed even in CNS and metabolized in liver (glucoronidation)
adverse efects of Zidovudine/AZT
anemia, neutropenia and hepatotoxicity.
Drug interactions exist - esp between those that compete for glucuronidation such as acetaminophen and benzodiazepines
Resistance can develop following a mutation in reverse transcriptase or inefficient kinase activation.
resistance to Zidovudine/AZT
Resistance can develop following a mutation in reverse transcriptase or inefficient kinase activation.
*approx 1/3 of patients will develop resistance with AZT monotherapy
what is nevirapine
binds and inhibits reverse transcriptase
- well abs and dsitributed throughout the body (including CNS) fetus and maternal milk) and metabolized by liver (glucoronidation)
adverse effects of nevirapine
- Adverse effects such as rash, psychiatric effects and hepatotoxicity
- Drug interactions can increase CYP3A4 which increases metabolism of certain drugs including itself, oral contraceptives, azoles, methadone and protease inhibitors.
Similar to zidovudine, resistance can occur if reverse transcriptase is mutated.
what is ritonavir
- inhibits HIV aspartyl protease: cleaves viral polyprotein itnp specific proteins
- drug is unpalatable (not pleasing to the taste) so it is often given with more palatable food (such as chocolate milk or pudding).
It does however have good bioavailability and it is metabolized by CYP3A4
adverse effects of ritonavir
nausea, vomiting, diarrhea, numbness, elevated liver enzymes and high blood glucose and lipid levels.
Resistance can develop via step-wise mutations in protease enzymes.
what is Maraviroc
CCR5 receptor antagonist that blocks binding of viral gp120 to CCR5 which prevents viral entry itno host cell
- approved in 2007 for patients previosuly treated with anti-HIV drugs
- reported to decrease viral load compared to placebo patients. Long-term effects of CCR5 inhibition is not known at this time, but hepatotoxicity and cardiovascular events have been reported.
what is raltegravir
- inhibits viral integrase by decreasing the transfer of viral DNA into the host genome.
It was approved 2007 for patients resistant to HAART drugs and in 2009 for all patients.
Clinical trials have reported a decrease in viral load earlier in patients taking raltegravir combined with HAART drugs compared to those taking HAART drugs alone.
The effect of raltegravir on latent HIV and potential elimination of the virus is currently under investigation.
what is the only approved treatment for COVid-19 patietns in hospital
remdesivir
- binds to viral RNA polymerase, inhibitng viral replication through premature termination of RNA transcription
- trils how that it sig reduced time in recovery in hospitalized COVID-19 pateints with mild to moderate symptoms
- unclear if it reduced long term morbidity after discharge from hospital or if more beneficial when combined with corticosteroids
*dont give if patient ahs impaired renal funciton
