36/37 anti-viral Flashcards
Antiviral Therapy A. _Therapy a. Adaptive b. Innate B. _ therapy a. DNA Viruses b. RNA Viruses c. Retroviruses
Immunologic
and chemotherapy
Families Of Viruses
- _ Viruses
- _ Viruses
- _ viruses
Families Of Viruses
- DNA Viruses
- RNA Viruses
- RNA Retroviruses
Diseases Produced By _
POX Viruses Small Pox
Herpes Viruses Chicken Pox (also known as Varicella Zoster, VZV)
Shingles (also known as VZV)
Herpes
Cytomegalovirus (CMV)
Adenoviruses Sore throat
Conjunctivitis
Papilloma Viruses Cervical Cancer
Skin Warts
Hepadnaviruses Hepatitis B
DNA Viruses
Chicken Pox (also known as Varicella Zoster, VZV) Shingles (also known as VZV)
Herpes
Cytomegalovirus (CMV)
Hepatitis B
Diseases Produced by _
Orthomyxoviruses Influenza A, B, C
Paramyxoviruses Measles, Mumps , Respiratory Syncytial Virus
Flaviviridae Hepatitis C
RNA Viruses
Diseases Produced by _
HIV-1 & HIV-2 AIDS
RNA Retroviruses
most viral transmission is from _
human to human
General Considerations about Viral disease
- Viruses can attack human, animal, plant, and bacterial cells (bacteriophage)
- More than 400 species of viruses infect man, but _ cause human disease
- Immunity against many viruses is _
only <50 cause human disease
immunity is lifelong
General Considerations about Viral disease
Different viruses can produce the same disease symptoms
(e.g. upper respiratory tract)
- Same virus can produce different diseases depending on the host’s immunity and age.
example _, a DNA virus, Herpesvirus family
30,000 children born with congenital
50-80% of adults in US infected by 40 years of age
Once in a person’s body, it stays there for life
Most infections are “silent”, without effect on the subject
Groups at risk of having disease:
-Unborn babies who are infected during pregnancy
-Immunosuppressed persons
ie HIV, transplant patients
Cytomegalovirus (CMV)
size of virus
Viruses are small:
Most viruses are 0.02-0.3 µm;
HIV is 0.1 µm (1000 A = 1/10,000 mm diameter)
A leukocyte is 15-25 µm in diameter,
an erythrocyte is 7-8 µm
Viruses are not cells, they are _
obligate intracellular parasites
Infection Process of Virus – Parasitism at many levels
- _ bind and contact cell- mediated by many molecules on cells
- may target a virus to a specific cell - Penetration & Uncoating
- Replication, Transcription & Translation
- Assembly
- Release of New Virus
- Secondary Infection of Other Cells
- Adsorption
Some drugs that affect adsorption to target cells:
Fuzeon, CCR5 antagonists for _, docosanol for _
Some drugs that affect adsorption to target cells:
Fuzeon, CCR5 antagonists for HIV, docosanol for HSV
Inhibition of viral _
Acyclovir, vidarabine, foscarnet, ganciclovir
DNA Polymerase (Synthesis of viral DNA)
DNA virsuses
Inhibition of viral _
Acyclovir, vidarabine, foscarnet, ganciclovir
DNA Polymerase (Synthesis of viral DNA)
DNA virsuses (Chicken Pox (also known as Varicella Zoster, VZV) Shingles (also known as VZV)
Herpes
Cytomegalovirus (CMV)
Hepatitis B
)
Points to know about adaptive immune reaction
- Antigen Presenting Cells (Macrophages, others) take up and digest antigens
- Processed antigen is presented on the cells surface in a complex with
Major Histocompatibility Proteins (MHC)
- Contact with a well-matched _Cell induces the Antigen Presenting Cell to
secrete Interleukin-1 - CD4+ T Helper Cell then produces _
- this activates various CD4+ T Helper cells to make other cytokines including Interferon
- These promote Cellular and Humoral Immunity:
CD4+ Helper
first produces IL1 then produces to Interleukin -2
Cellular Immunity
- Killer cells destroy virus-infected cells, reducing the virus population.
Humoral Immunity
T Helper cell contacts B cell holding the correct antigen with MHC
T Helper cell produces other cytokines that stimulate the B cell to reproduce and
to make antibodies
_(from immune system has 2 effects:
A. activates killer cells
B. induces resistance of other host cells to virus
Interferon
_ Function
- Binds antigen
can neutralize it
- Fc stem allows cells to recognize the antigen-antibody complex so it can be
phagocytosed and destroyed (there’s an Fc receptor on the host cell).
Antibody
Antiviral Therapies Immunologic Therapy using the Adaptive Immune System
_ = vaccination with Antiviral Vaccines - Administration of antigen to induce cellular and humoral immunity - Takes time (ie weeks) to develop Ideal Immunogen - prevents disease - low frequency of immunization required - non-toxic
Use: Prophylaxis
Active Immunization
Mechanism
Memory T and B cells activate when exposed to authentic virus antigens.
- Cellular and humoral immunity are activated
Cellular - Killer cells remove virus infected cells
Humoral
- Antibodies may coat virus, induce opsonization and phagocytosis by
macrophages/neutrophils and others.
- Immunoglobulins could interfere with adsorption if they react with
the correct surface antigen
Immunologic Therapy using the Adaptive Immune System
_ - Administer preformed Antiviral Immunoglobulins
Mechanism: Injected antibody coats virus,
Induces opsonization and phagocytosis.
Use: Treatment and Prophylaxis
Onset of Protection: Rapid
Duration of Protection: 1-3 months
Passive Immunization
Good for - individuals unable to make antibodies
- prevention of disease when time does not permit active
immunization
Sources: a. Engineered antibodies
b. Serum or plasma from animal or human donors
Problems: Allergy, hypersensitivity
(histamine release anaphylaxis or other symptoms)
- Less of a problem with human derived products
- Highly purified rodent and rabbit products seem to be safest animal products
- human antibodies generally have a longer half-life than anima
Immunologic Therapy from the Innate Immune System– Interferon (IFN)
Interferon gamma is the one produced in the _ immune response
Other interferon types (known as Type I) are produced by _ immune response
One of these is used as a drug
Interferon gamma - adaptive
other type 1 - innate response
Innate Immune System
type 1 interferon is produced by 2 types of cells: Specialized Interferon Producing Cells and Most Normal Cells
when it is secreted to act on other cells what does it induce
Induces many
genes to promote
resistance of
uninfected cells
innate immune system - type 1 interferon
_ Cells such as plasmacytoid dendritic cell precursors
(or Natural Interferon Producing Cells). These express receptors that recognize viral
DNA and RNA molecules (Toll-like receptor (TLR)-7 and TLR9), and are specialized in
rapidly secreting massive amounts of type 1 interferon following viral stimulation.
Viral glycoproteins also activate production via non-TLR paths,
maybe some receptor for this
Specialized Interferon Producing
. Most Normal Cells Intracellular Double stranded RNA Receptors Protein Kinase R (PKR) Retinoic acid-Inducible Gene 1 (RIG-1) Activated by dsRNA Induce IFN production
Interferon Action
- Interferon Circulates and activates interferon receptors on other cells
- This induces expression of many genes that promote _
resistance to many viruses
Interferon-Induced Genes Act Against Viruses
A. They can inhibit
1. Viral Penetration and Uncoating
2. Viral Transcription
3. Viral Translation
4. Viral Protein Glycosylation required for processing and maturation of virus
B. Interferons also activate Killer Cells (Natural and CD8+ T-Killers) to attack
Virus-infected cells
Interferon-α is the one currently used as a therapeutic
spectrum?
resistance - due to Ab’s and anti-interferon signaling
toxcity - flu-like symptoms, fever
: Uses Hepatitis-B, C
Hepatitis- D, chronic but not acute infection
Papilloma virus (warts): intralesional injection
Most RNA viruses, Most DNA viruses, Retroviruses
broad spectrum
Goal - Selective Toxicity to the virus without harming host
chemotherapy
Selective targeting depends on the specific Viral Life Cycle:
- Attachment
- Uncoating
- Viral Thymidine Kinase
- Viral DNA polymerase or Viral Reverse Transcriptase
- Viral Integrase and Proteases
- Release Process
- Immune Modulators
Spectrum of Activity of Antiviral Agents
most drugs generally work on viruses of _ genome type
one type (either DNA, RNA, or retro, usually one drug not good for different families)
4 DNA genome virus’s
Herpes Simplex (HSV)
Varicella Virus/Herpes Zoster/Chicken Pox (VZV)
Cytomegalovirus (CMV)
Hepatitis B (HBV) – but also has a reverse transcriptase step
2 RNA genome viruses
Influenza Hepatitis C (HCV)
2 retroviruses RNA genome
Human Immunodeficiency Virus -1 (HIV-1)
Human Immunodeficiency Virus -2 (HIV-2)
Drugs for DNA Viruses
1. Inhibitors of viral DNA polymerase and/or Hepatitis B Reverse Transcriptase
Acyclovir (Zovirax, Sitavig)
Valacyclovir (Valtrex)
Base analogs - Resemble bases or parts of them
Lamivudine (3TC, Epivir)- base analog inhibitor of viral _
Hepatitis B Reverse Transcriptase
Drug affecting _ - Ribavirin (Virazole)
RNA
Inhibitor of _ attachment - Docosanol
HSV
All share OH group and need to be phosphorylated to work
Mono to di to triphosphate (tri works as drug)
Base analogs - inhibitors of viral DNA polymerase and/or reverse transcritase (hep B)
Mechanism of Action
-Phosphorylated by Viral Thymidine Kinase»_space;> human Kinase
- cellular enzymes make the triphosphate,
- increases accumulation of drug in infected cells
-triphosphate inhibits viral DNA polymerase»_space;> human DNA polymerase
- competes with dGTP
- lacks 3’OH; when incorporated into DNA terminates chain and irreversibly
inactivates viral DNA polymerase
Acyclovir
Selective metabolic
activation in virus-
infected cells
Competitive Inhibition - for GTP
Incorporation into DNA - Viral DNA Polymerase Cannot Add Another Base - Causes Chain Termination - Structure inhibits DNA pol
Acyclovir (Zovirax; Sitavig) spectrum?
Herpes viruses mainly
HSV > CMV
Agent of Choice for HSV-1, HSV-2, VZV
_ drug
- L-valine ester prodrug converted completely to acyclovir
- Better absorbed than acyclovir
Mechanism of Action
-Phosphorylated by Viral Thymidine Kinase
-cellular enzymes make the triphosphate,
- increases accumulation of drug in infected cells
-triphosphate inhibits viral DNA polymerase»_space;> human DNA polymerase
- competes with dGTP
- lacks 3’OH; when incorporated into DNA terminates chain and irreversibly
inactivates viral DNA polymerase
Spectrum Herpes viruses mainly
HSV > CMV
Resistance
1. Deficient or Mutant Viral Thymidine Kinase
2. Mutant viral DNA Polymerase
TOX Well Tolerated
USE Agent of Choice for HSV-1, HSV-2, VZV
Valacyclovir (Valtrex)
Mechanism Same as acyclovir
Spectrum Same as acyclovir
Resistance Same as acyclovir/Cross-Resistance
Use Same as acyclovir
base analog drugs _ and _ developed to become more active against CMV
Ganciclovir (Cytovene)
Valganciclovir (Valcyte) - L-valyl ester prodrug of ganciclovir
Mechanism Herpes: viral thymidine kinase performs first phosphorylation, then
cellular kinases make di and triphsophate as for acyclovir,
In CMV: UL97 Kinase phosphorylates the drug first
Acyclovir Adefovir
Cidofovir Valacyclovir
Penciclovir Famciclovir
Ganciclovir
all of these drugs are anti viral and belong to _ class of drugs
Base Analogs lacking sugar ring
Inhibitors of viral DNA polymerase and/or Hepatitis B Reverse Transcriptase
In CMV: _ phosphorylates the drug first.
_ triphosphate
-competitively inhibits dGTP on DNA polymerase
- inhibits elongation after incorporation into DNA
10x greater concentrations of activated drug in CMV-infected cells vs uninfected cells
UL97 Kinase
Ganciclovir triphosphate
Most effective against CMV
CMV»HSV
Resistance Mutation of Viral DNA Polymerase
CMV: UL97 Mutations
Thymidine Kinase Mutations
- Cross Resistance With Acyclovir
USE Prophylaxis & Treatment of CMV
- especially useful in transplant patients
_ is a DNA virus
BUT replication proceeds through reverse transcription of a pregenomic RNA
intermediate
Hepatitis B (HBV) (liver)
HBV Reverse transcriptase (RT) is about 50% homologous with HIV RT
Like HIV, HBV RT can be selectively targeted with several _ drugs
Base Analog Drugs
Lamivudine (3TC, Epivir)
Activated intracellularly to triphosphate by cellular enzymes.
Competes with dCTP to inhibit Reverse Transcriptases
Lacks 3’OH in correct orientation necessary for continued polymerization of DNA
When incorporated into DNA causes chain termination
Used against Both Hepatitis B and HIV
Base analog drug for HBV
_
Activated intracellularly to triphosphate by cellular enzymes.
Competes with dCTP to inhibit _
Lacks 3’OH in correct orientation necessary for continued polymerization of DNA
When incorporated into DNA causes chain termination
Used against Both Hepatitis B and HIV
Lamivudine (3TC, Epivir)
competes with dCTP to inhibit Reverse Transcriptases
and lacks 3’prime OH for DNA polymerization
_ drug affects RNA
Mechanism: -phosphorylated by cellular enzymes
-RMP Inhibits GTP synthesis by inhibition of inosine 5’-
Phosphate dehydrogenase
-RTP Inhibits usage of mRNA interfering with GTP capping of
5’end of mRNA
-Inhibits RNA polymerase decreasing mRNA and protein synthesis
Basically inhibits production and use of RNA
Ribavirin (Virazole)
Spectrum Unusual since it is Broad Spectrum; Affects many DNA & RNA viruses
Ribavirin (Virazole) affects _
spectrum?
affects RNA
Spectrum Unusual since it is Broad Spectrum; Affects many DNA & RNA viruses
_
Inhibits attachment of enveloped viruses to cells
Active against:
DNA viruses: HSV 1 and 2, human herpesvirus-6, CMV
RNA Viruses: Influenza and RSV
Not active against poliovirus, which does not contain a lipid envelope
USE: Topical cream (10%) for oral HSV works if used within 12h of prodromal
symptoms on face
Docosanol (Abreva, Behenyl Alcohol
_Viral Diseases
Influenza
Hepatitis C
RNA
Hemagglutinin/neuraminidase (HN) complexes mediate attachment of influenza
- HN in a complex with the Fusion Protein (F) binds to sialic (= neuraminic) acid on
the ends of glycoprotein sugar chains.
- Induces conformation change in F protein triggering virus-cell fusion
RNA Viral Influenza
Types A, B and C
3 forms of a specific antigen used to classify human influenza viruses as A, B or C
_type infect Animals and Humans
_ type infects Humans, and symptoms are mild or subclinical.
A and B infect Animals and Humans
C only infects Humans, and symptoms are mild or subclinical.
There are many antigenic variants of A and B
Spikes on viral surface of A, B and C
Hemagglutinin [H], Neuraminidase [N] and Fusion [F] proteins
Within Type A
Defined by the H and N components of the spikes
- 16 known H subtypes
- 9 known N subtypes
- Many different combinations of H and N proteins are possible
- Each combination represents a different subtype:
Avian Flu of 2007-8: H5N1; 1918 Spanish Flu and 2009 Swine Flu: H1N1
Symptoms of Influenza in Humans
Fever, cough, sore throat, and muscle aches, acute _
Most dangerous consequence: Secondary bacterial pneumonia
Less common but dangerous: viral pneumonia
acute respiratory distress
Flu is the most frequent cause of pneumonia in healthy adults
viral pneumonia less common
Flu can: Increase susceptibility to bacterial infections in lung and ears:
Exacerbate asthma
Worsen Chronic Congestive Heart Failure
influenza Transmission
Contact with fluids can transmit
Pandemics, however, depend on efficient _ transmission and infection:
- Virus particles bind cells of respiratory epithelium
- Neuraminidase present on the virus particles, and some bacteria, aids release of
virus from mucous and epithelial cells
- Aerosolized droplets spread particles to other individuals.
efficient respiratory transmission and infection
Drugs For Viral Influenza (an RNA Virus)
Target 1: _ Allows Genome Release within cells– When virus enters acidic vesicle inside a cell, M2 (influenza A) or BM2 (influenza B) channels are induced to open
_ drugs block the M2 channel, but not the BM2 channel
M2 protein
- Ribonucleoprotein complex dissociates
- Hemagglutinin [H] conformation changes allowing adherence to vesicle membrane
- Genome is released into cytosol
Adamantane
Adamantanes:
Amantadine (Symmetrel); Rimantadine (Flumadine)
Mechanism: Prevent uncoating of _ virus after viral entry into
host cell and release
Drugs bind and inhibit action of viral M2 protein ion channel
Inhibits acidification of internalized vesicle
1. Inhibits dissociation of ribonucleoprotein complex
2. Inhibits acid-induced hemagglutinin conformation changes that would
allow binding of virus to cellular receptors
Spectrum: Influenza A only
prevent uncoating of influenza A
USE: 1. Seasonal Prophylaxis: 70-90% effective
2. Treatment within 48 hrs of flu onset may decrease duration of illness
3. Ability to decrease complications questionable
4. To protect high-risk patients immunized after flu epidemic outbreak
5. Prophylactic for immunodeficient patients responding poorly to flu vaccine
Resistance: Inherent resistance is rare (1%), but
Drug rapidly selects for M2 mutants in 50% of subjects
Resistant forms can replace original virus in 2-3 days
Cross-resistance between these amantadine and rimantidine is seen.
Drugs For Viral Influenza (an RNA Virus)
Target 2
_ in the HN (Hemagglutinin [H], Neuraminidase [N] ) complex mediates release
- hydrolyzes terminal neuraminic (= sialic) acids from proteins and other host cell
membrane molecules conjugated with sugars.
Neuraminidase
Viral Neuraminidase of Influenza A & B normally
- Cleaves Neuraminic Acid from Receptors for Viral Hemagglutinin in Host Cell
Membranes
- Cleavage of neuraminic acid disrupts binding of viral hemagglutinin to cell
- Allows Viral Release
Inhibitors prevent release of virus
- Virus Aggregates on Cell Surface and Fails to Spread Within Respiratory Tract
Spectrum - Influenza virus A & B
Resistance: Hemagglutinin and/or
Neuraminidase mutants
USE -Decrease Days of illness by 1-2 days
Prophylaxis decreases flu incidence by 60-70%
Oseltamivir, at least, does not actually prevent secondary bacterial infections
Zanamivir (Relenza)
Oseltamivir (Tamiflu)
Peramivir (Rapivab)
Inhibitors of Neuraminidase in the HN complex mediates release (blocking release)
Zanamivir (Relenza)
Oseltamivir (Tamiflu)
Peramivir (Rapivab)
what are they used for
Influenza virus A & B (RNA)
Inhibitors of Neuraminidase - blocking release of virus
HCV Targets Exploited
1. Protease: non structural protein NS3-4A
2. RNA Polymerase: non structural protein NS5B
3. Non structural protein NS5A: aids viral replication, and assembly in some way
There has been rapid recent development of agents and combinations, even without
interferon, to hit these targets.
Hepatitis C Serine Protease (NS3-4A) Inhibitors
2nd generation:
Glecaprevir – is in the combination with Pibrentasvir in Mavyret
Glecaprevir – is in the combination with Pibrentasvir in Mavyret
used to tx?
HCV -hep c
NS3-4A is a serine protease
- A heterodimer of the N-terminal serine protease domain of the NS3 protein
(catalytic subunit) and NS4A cofactor protein (activation subunit, membrane bound).
- Cleaves HCV polyprotein precursor at four sites
This produces several enzymes and structural proteins for the virus
Mechanism
Inhibition of protease prevents assembly of HCV
Glecaprevir – is in the combination with Pibrentasvir in Mavyret
Spectrum: Specific for HCV
Note: some agents are selective for particular HCV genotypes
Ie 2nd generation: Simeprevir and Paritaprevir are effective only against
genotype 1
Glecaprevir – is in the combination with Pibrentasvir in Mavyret
Hepatitis C Polymerase (NS5B) Inhibitors
NS5B: An RNA-dependent RNA polymerase responsible for the complete copy of the RNA
viral genome
Prodrug of a _
Metabolite is incorporated in RNA and terminates chain inhibiting HCV replication
Base Analog
Sofosbuvir (Sovaldi)
Base Analog
Sofosbuvir (Sovaldi) used to tx
Hepatitis C
Polymerase (NS5B) Inhibitors (blocks replication)
Non-nucleoside inhibitor of NS5B HEP C
_
binds at sites other than nucleotide site to allosterically inhibit NS5B
Dasabuvir
NS5A Inhibitors
_ – is in the combination with Glecaprevir in Mavyret
NS5B: An RNA-dependent RNA polymerase responsible for the complete copy of the RNA
viral genome
Pibrentasvir
NS5A is a protein required for HCV replication and assembly. It is not known how it works in
these processes.
NS5A has 4 functional domains:
1. N-Terminus: may bind to endoplasmic reticulum
2. Domain I binds zinc and RNA. It may tether HCV RNA to cell membranes
3. Domain II binds many host proteins. Some of these affect RNA synthesis.
4. Domain III is required for viral assembly
Mechanism – disrupt replication and assembly
Mavyret: _ and _
specific for HCV
protease inhib and NSB inhib
Glecaprevir (Hepatitis C Serine Protease (NS3-4A) Inhibitors - Inhibition of protease prevents assembly of HCV
and Pibrentasvir (NS5A Inhibitors (inhibs organization and scaffold)
Mavyret: _ and _
specific for HCV
protease inhib and NSB inhib
Glecaprevir (Hepatitis C Serine Protease (NS3-4A) Inhibitors - Inhibition of protease prevents assembly of HCV
and Pibrentasvir (NS5A Inhibitors (inhibs organization and scaffold)
Life Cycle of an RNA Retrovirus (HIV)
HIV gp120 attaches to CD4 T helper cells via binding to the CD4 molecule and to receptors
for cytokines that are recognized by the Th cell, CCR5 and CXCR4. These receptors
normally allow T helper cells to respond to cytokines and interleukins.
Both CD4 and CCR5 are needed for optimum virus interaction and internalization
CD4/CCR5 Receptors are on: _ _ _
HIV gp41 is induced to fold back on itself, which critical for fusion of HIV with target cell
membrane – new fusion inhibitor drugs block this step (see later).
Persons with a mutation in both copies of CCR5 are resistant to HIV infection.
Th Lymphocytes
Monocytes/Macrophages
Neurons in CNS
HIV retro virus
Viral strains from patients with early stage disease usually use _ coreceptors
CCR5 coreceptors
CXCR4: About one-half of strains from patients with advanced immunosuppression also use
the CXCR4 coreceptor alone, or CCR5 plus CXCR4 receptors (“dual/mixed” tropic
viruses) for attachment to host cells.
HIV is diversifying by mutation of its genes over time.
HIV Subtypes
Two Families of HIV: HIV-1 and HIV-2
Genetically distinct, ~ 50% homologous
_ - Specialized sequence at each end of the genome
Functions :
1. Used for integration into the host genome by viral integase
- In the host DNA, the LTR sequence is recognized by the HIV tat protein,
and by host transcription factors, such as NFkB.
This drives transcription of the HIV genome in the host DNA
LTR = Long Terminal Repeat
ANTIRETROVIRAL DRUGS
Nucleoside and Nucleotide Reverse Transcriptase Inhibitors
example?
Lamivudine (3TC, Epivir) – also for HBV
also have Non-Nucleoside reverse transcriptase inhibitors
Protease Inhibitors – inhibit processing/assembly
Fusion/adhesion inhibitor
CCR5 antagonist:
Integrase Inhibitor
HIV Resistance to individual agents usually occurs
It usually develops quickly (within <2 yrs in 50% of patients)
- It is essential to limit the development of resistance.
Note that when resistant HIV is transmitted, the recipient is drug-resistant.
- Resistant mutations develop in drug targets, such as Viral Protease, Reverse
Transcriptase and Integrase reducing their inhibition by drugs
Combating HIV Resistance
1. _ reduce the emergence of resistant forms.
2. _ inhibitors may slow down mutagenesis and evolution of HIV
- Multidrug combinations
2. Reverse Transcriptase inhibitors
ANTIRETROVIRAL DRUGS - HIV
- All resemble nucleosides
-Activated intracellularly to triphosphates by cellular enzymes. - Lack 3’OH necessary for continued polymerization of cDNA.
- Reverse transcriptase makes faulty or incomplete DNA copies of HIV RNA - Generally work on HIV-1 and -2
- Can cause hepatic damage, steatosis and lactic acidosis at a low frequency,
but this can be fatal;
Alcohol consumption probably enhances risk of hepatic damage.
Nucleoside/Nucleotide Inhibitors of Reverse Transcriptase (NRTI)
Generally work on HIV-1 and -2
There are some combinations of NRTI that are generally avoided within this group:
a. Agents that use identical kinases for metabolic activation
b. Agents that each cause the additional toxicities of pancreatitis and sensory neuropathy
c. Similar base analogs (ie two cytosine analogs may act similarly
First effective anti-HIV drug - 1987
1. Phosphorylated
First: by cellular Thymidine Kinase
Second: by Thymidylate Kinase
Third: by Nucleoside Diphosphate Kinase
2. Should not be combined with other agents that compete for phosphorylation by the same
thymidine kinase – might mutually antagonize
(Stavudine (zerit) is an example)
3. Additional TOX: Bone marrow suppression (Anemia, neutropenia)
Nucleoside/Nucleotide Inhibitors of Reverse Transcriptase (NRTI)
Notes on Combinations to avoid:
Stavudine and Zidovudine: compete for activation, and both are thymidine analogs
Nucleoside/Nucleotide Inhibitors of Reverse Transcriptase (NRTI)
Cytosine analog: competes with dCTP for incorporation into viral cDNA
Converted into triphosphate by cellular enzymes causing polymerase inhibition
and is incorporated into DNA causing chain termination
Lacks 3’OH in correct orientation necessary for continued polymerization of DNA
Also inhibits HBV Reverse Transcriptase:
FYI: Pancreatitis is reported rarely in children: possible concern for combination with ddI and
Stavudine
Spectrum: Hepatitis B and HIV
USE: HIV and HBV
NOTE: Hepatitis B could reemerge more severely if present when drug is discontinued
Lamivudine (3TC, Epivir)
Summary of Spectrum of _
- All effective against HIV 1 and 2
- Some Agents are active against hepatitis B virus (HBV) in vitro
Nucleoside Reverse Transcriptase Inhibitors (NRTI)
retrovirus drugs
_ drugs
Class Properties
1. Do not require intracellular phosphorylation - Do not resemble nucleosides
2. Bind to reverse transcriptase adjacent to active site
- Causes a conformational change in the active site, inhibiting it.
3. Spectrum = retrovirus HIV-1, but not HIV-2
4. Cross placenta and present in milk.
5. Cause rash (sometimes severe)
6. Metabolized by hepatic Cytochrome P450, resulting in many drug interactions
(including with protease inhibitors)
7. Rapid development of resistance when used alone.
Generally due to mutations in Reverse Transcriptase
Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI)
Skin rash (16%) - sometimes severe and fatal; dose-limiting effect in ~7% of cases; Can be minimized by starting with low dose and then escalating it
retrovirus drugs
_ is Dimer of two 99 amino acid subunits
2. Each contributes an aspartic acid to the active site
3. Human aspartyl proteases are monomeric and 1000 fold less sensitive to
HIV protease inhibitors
4. HIV Protease cleaves gag-pol polyprotein producing
1. Active enzymes
A. Reverse Transcriptase
B. HIV Protease
C. Integrase
2. Structural Proteins (p17, p24, p9, p7)
Original HIV Protease Inhibitors resemble the transition state
of cleavage sequences in Gag-Pol.
(Enzyme prefers to cut phe-pro in the polyprotein)
Non-peptidic structures: Nelfinavir, Tipranavir
6. Inhibition prevents maturation of virus
HIV Protease
HIV Protease Inhibitors In combination with reverse transcriptase inhibitors they markedly lower peripheral blood
levels of HIV, and prolong survival.
2. Not a cure since lowering dose leads to resurgence of HIV blood levels.
3. Most work on HIV-1 and 2 (some may be better against HIV-1)
4. Orally administered
. In combination with reverse transcriptase inhibitors they markedly lower peripheral blood
levels of HIV, and prolong survival.
2. Not a cure since lowering dose leads to resurgence of HIV blood levels.
3. Most work on HIV-1 and 2 (some may be better against HIV-1)
4. Orally administered
Resistance
1. Resistance develops quickly when used alone.
2. Mutation in the protease enzyme of HIV leads eventually to drug resistance.
3. All transported by PGP multidrug resistance transporter (MDR-1):
Causes resistance and limits penetration of BBB (P-glycoprotein in endothelium).
4. Cross-resistance among protease inhibitors is probable.
Kinetics
Metabolized by hepatic cytochrome P450 leading to drug interactions
HIV Protease Inhibitors
You only need to know the principle of inhibiting HIV protease to stop viral assembly
Blocking HIV entry is based on the function of _
gp120/gp41
41 folds and interacts with
target cell membrane
Fusion inhibitors and CCR5 antagonists disrupt _ mechanism
mechanism of HIV entry
HIV gp120 Binds CXCR4 or CCR5/CD4 complex on target cell gp41 folds and interacts with target cell membrane
Virus coat fuses
with cell membrane
blocks HIV from entering healthy human immune cells
- active against strains that have become resistant to already available medications.
- Synthetic peptide corresponding to a repeat sequence in HIV gp41
Competes with endogenous HR2 for binding to HR1
- Antagonizes folding of gp41
Fusion Inhibitors
retrovirus
Selective, reversible _coreceptor antagonist
Prevents V3 domain of gp120 from binding CCR5 receptor
Prevents gp120 conformation change, inhibiting HIV entry
CCR5 coreceptor antagonist
Integrase inhibitors for HIV drugs
- Integrase forms complex with the viral DNA _
- Terminal dinucleotide from each end of the viral DNA is removed
by endonuclease processing. - Viral DNA ends are covalently linked to the cellular DNA (Strand Transfer).
This is the step that is blocked
LTRs
integrase inhibs - Mechanism: Strand transfer (step 3) is antagonized
USE: Effective against HIV-1 and 2
A final word on HIV Vaccine Problems
1. Vaccines provoke an antibody response (prophylaxis, active immunization), sera are
ready-made antibodies (treatment, passive immunization).
HIV infection does provoke an initial antibody response, but the antibodies have been
powerless against infection.
2. Viral diseases for which vaccines exist are transmitted by free viruses. HIV is transmitted
in cells (semen, blood). Cell to cell transmission of HIV results in minimal transit in
blood in contact with HIV antibodies. Antibodies do not penetrate cells.
3. HIV can multiply at the colorectal portal of entry without interference by antibodies.
4. HIV mutations make it difficult to produce active vaccines. Many variants have been
identified and a single mutation can eliminate antigen.
5. Vaccines made from Lab-Grown HIV represent the non-mutated strains.
6. HIV vaccines tested so far have been _
ineffective
