Transcript File - Riske Science

Lesson 8: Antivirals
Thursday, March 17, 2016
Understandings
• Viruses lack a cell structure and so are more
difficult to target with drugs than bacteria.
• Antiviral drugs may work by altering the cell’s
genetic material so that the virus cannot use it
to multiply. Alternatively, they may prevent
the viruses from multiplying by blocking
enzyme activity within the host cell.
Applications and Skills
• Explanation of the different ways in which
antiviral medications work.
• Description of how viruses differ from bacteria.
• Explanation of how oseltamivir (Tamiflu) and
zanamivir (Relenza) work as preventative agents
against flu viruses.
• Comparison of the structures of oseltamivir and
zanamivir.
• Discussion of the difficulties associated with
solving the AIDS problem.
Viruses
• Viruses are sub-microscopic and can only be studied with
an electron microscope
• They come in all shapes and sizes
• They are such small and simple structures that there is
debate about whether
they can be classified as living organisms in their own right.
They contain only two viruses. main components, protein
and nucleic acid (either RNA or DNA), have no cellular
structure, and are only capable
of reproducing inside another
living cell.
Virus Structure
• Viruses have a core consisting of their genetic
information (carried in the form of either DNA or RNA)
which is surrounded by a protein coat known as a
capsid.
• This capsid consists of identical protein subunits, called
capsomeres, and its role is to protect the genetic
information in the core.
• The capsid and genetic material together are called a
nucleocapsid.
• Some viruses, such as the human immunodeficiency
virus (HIV), also have a lipid envelope that surrounds
the nucleocapsid
Viruses
• Viruses take over the function of another cell,
the host-cell, and use that other cell to carry
on reproduction
How does the body fight back?
• The body’s defense system usually responds to
viral infections by producing specific antibodies,
which act against a virus in the immune
response. This often leads to protection, known
as immunity, against repeated infections with the
same virus.
• But sometimes the virus is not completely
eradicated from the body and remains dormant
in cells. This can cause a flare-up on another
occasion, such as some herpes infections which
cause cold sores.
Viruses Cause Many Deaths
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Flu
Measles
Meningitis
Polio
HIV
Ebola
Avian Flu
A Difficult Fight
• Treating viral infections is particularly difficult because the
viruses live within host cells and so cannot be easily
targeted.
• Antibiotics such as penicillin are effective against bacteria,
because they can target a structure such as a cell wall, but
there are no equivalent structures to target in viruses.
• Another problem is the speed at which viruses can multiply,
so that they are often spread through the organism by the
time that symptoms appear.
• In addition, virus particles have a tendency to mutate
rapidly, which means that they make small changes in their
genetic material, and this changes their susceptibility to
drugs.
Vaccines
• Vaccines were first introduced in the 18th
century, and today are a major aspect of
preventative healthcare, known as
prophylactic treatment.
• Vaccines work by stimulating the body to
prepare specific antibodies which can give
immunity. Successful vaccination programs
have reduced the incidence of diseases such
as cholera, polio, and measles.
Limitation To Vaccines
• Why do we need a flu shot every year? Since
viruses mutate so rapidly, vaccines are not
always effective forever.
• In addition, sometimes our immunity wanes
as we age so we need booster shots to ensure
continued protection
Antiviral Drugs
• When vaccines do not exist or are not
effective, we must rely on antiviral drugs to
treat viral infections
Antivirals – How Do They Work?
• Some alter the genetic material within cells – once inside a cell, the drug
is converted into an active metabolite that becomes incorporated into the
growing DNA strand (needed for viral replication) halting its synthesis. An
example of a drug that acts in this way is aciclovir (acyclovir), which is used
to treat cold sores; it stops viral DNA replication and so stops the virus
from multiplying.
• Some inhibit the activity of enzymes within the host cell that are
necessary for the formation of new viruses. An example is indinavir, which
is used in AIDS treatment; it inhibits the HIV enzyme protease, which is
essential to the assembly of functional new HIV viruses.
• Some stop the viruses from infecting host cells by preventing them from
binding to the host cell surface and gaining access into the cell. Some
drugs used to treat AIDS work in this way.
• Some prevent the virus from leaving the host cell so that it cannot infect
other cells – see oseltamivir and zanamivir below.
Lesson 9: Influenza
Friday, March 18, 2016
Influenza
• We usually do not think of getting the flu as a
death sentence but roughly half a million
people each year die of the flu
• Infectious disease doctors are constantly on
the lookout for the mutation that will cause a
pandemic – a global outbreak with a high risk
of casualties
Influenza A and B
• Flu is causes by two different types of viruses
– influenza A and B
• They are spherical viruses and have RNA as
their genetic material.
• Flu viruses have specific proteins on their
surface, of which two play a key role in their
life cycle.
Flu Proteins
• 1 Hemagglutinin (H) is a glycoprotein that
enables the viral particle to ‘dock’ with the host
cell before it enters.
• 2 Neuraminidase (N) is an enzyme that catalyses
a cleavage reaction which allows the new viral
particles to escape from the host cell and spread
infection. The enzyme snips off a type of sugar
molecule, sialic acid, from glycoproteins on the
surface of the host cell membrane.
Attacking Flu
• If the action of either of these viral proteins was
affected, it would evidently interrupt the viral life cycle.
Of the two, neuraminidase seems to be a better target
for drug design and so it has become a focus for
research.
• Neuraminidase binds to its reactant sialic acid, the
substrate, at a specific region known as the active site.
It is this binding between enzyme and substrate that
gives the catalytic action, as it provides a reaction
pathway of lower activation energy. Chemicals that
interfere with this binding are called inhibitors and
usually have a specific with the enzyme.
Tamiflu Action
• https://www.youtube.com/watch?v=0qCTyKrh
VWc&feature=youtu.be
New Drugs
• The three-dimensional structure of neuraminidase
became known through X-ray crystallography in 1993,
including details on its active site. This enabled
researchers to design a molecule which could bind at
the active site and so block the binding of substrate
and act as an inhibitor.
• The first neuraminidase inhibitors were designed by a
team in Australia, and led to the production of
zanamivir (Relenza), which was approved for use in
2000. It was closely followed by the production of
oseltamivir (Tami u).
Sialic Acid
Lesson 10: HIV/AIDS
Monday, March 21, 2016
HIV/Aids
• https://www.youtube.com/watch?v=oYwtMor
ZbdY
• http://www.pbs.org/wgbh/pages/frontline/vi
deo/flv/generic.html?s=frol02s461q6b&contin
uous=1
HIV/AIDS
• AIDS was first recognized in 1981 and was
found to be caused by the HIV virus a few
years later.
• There are now believed to be more than 34
million people infected with HIV worldwide,
and approximately 2 million deaths occur each
year from AIDS.
HIV
• HIV primarily infects vital white blood cells in the immune
system. These cells are called CD4+ T cells.
• The virus binds to specific receptor proteins on the cell
surface and then penetrates the cell.
• HIV is a retrovirus, which means that its genetic material is
in the form of RNA rather than DNA.
• The virus releases its RNA into the cell and the enzyme
reverse transcriptase controls the synthesis of viral DNA
from this RNA. The viral DNA integrates into the cell’s own
DNA and replicates with it when the cell divides. Viral
particles are produced within the host cell, and are
released in large numbers when the cell dies.
Why is HIV Hard To Combat?
1. The virus destroys helper T cells, the very cells in the
immune system that should be defending the body
against the virus.
2. The virus tends to mutate very rapidly, even within a
patient. It is thought that there is more variation in
HIV in a single patient than in the influenza virus
worldwide in a year. These variations mean that the
virus ‘escapes’ the immune response, so the patient
has to make a response to the new virus.
3. The virus often lies dormant within host cells, so the
immune system has nothing to respond to.
Antiretrovirals (ARVs)
• Antiretroviral drugs target and interrupt the
following different stages in the HIV life cycle:
– binding and fusion of the virus to the receptor on
the CD4 cell membrane
– reverse transcription of viral RNA to DNA in the
host cell
– integration of viral DNA into the host chromosome
– release of new viral particles by budding from the
host cell surface.
How AZT Works
• http://www.hhmi.org/biointeractive/aztblocks-reverse-transcriptase
Triple Cocktail
• Of these targets, inhibitors of the
viral enzyme reverse transcriptase are the most
widespread. They include drugs such as AZT, also known as
zidovudine, which was the first antiretroviral drug to be
approved.
• It has been found that the best results occur when a
combination of different ARVs is used. Combination
treatments typically include two different reverse
transcriptase inhibitors plus a third drug, all of which can be
taken as a single pill once daily. This regimen has been
referred to as the “triple cocktail.”
• The cost for most combination treatments is approximately
$12,000 per patient per year.
AIDs Vaccine
Intense research on developing a vaccine for
HIV/AIDS is ongoing. There are some hopes that a
therapeutic vaccine may be possible to help control
the infection in people who are HIV-positive. But
the development of a preventative vaccine that
would give immunity to people who are HIVnegative has so far not been possible. This is mainly
because of the problem of the variable nature of
the virus within cells, and the fact that the immune
response seems to act too slowly in the case of HIV
infection.
•
Truveda
To date, the only prophylactic treatment for the prevention of
HIV infection in high-risk individuals is Truveda
• Truveda is a fixed-dose combination of two antiretroviral drugs
used for the treatment of HIV/AIDS.
• In studies, tenofovir reduced the incidence of HIV infection,
especially in high-risk individuals but produced conflicting
results in other studies. One study estimated through
mathematical modeling that daily intake of Truvada could
potentially achieve a 99% of risk reduction of contracting HIV in
high risk individuals. Another study, iPrEX OLE, showed overall
PrEP effectiveness of 50% rising to 100% when participants took
the drug four or more times per week. A Cochrane review found
that both tenofovir alone, as well as the tenofovir/emtricitabine
combination, decreased the risk of contracting HIV by 51%.
• In conclusion, PrEP has not been shown to make HIV 100% nontransmittable and is currently only recommended for high risk
individuals
HOMEWORK
• Please review your notes on nuclear chemistry
from Regents, particularly writing nuclear
equations and calculating half-life
• I am not going to reteach this material in the
interest of time
Questions
Answers