15
Option D: Medicinal chemistry
[butanoate ion] = 0.15 mol dm–3
The molar mass of potassium butanoate is 126.12 g mol–1
1.00 dm3 of 0.15 mol dm–3 solution = 0.15 mol × 126.12 g mol–1 = 19 g
So 19 g potassium butanoate should be added to 1.00 dm3 of 0.10 mol dm–3
butanoic acid.
The following assumptions were made:
• [butanoate ion]equilibrium = [potassium butanoate]initial
• [butanoic acid]equilibrium = [butanoic acid]initial
• no volume change occurs on mixing the solution
Exercises
13 Suggest why the action of drugs in lowering the production of stomach acid is considered to be
indirect in the case of H2-receptor antagonists, but direct in the case of gastric proton pump inhibitors.
14 Magnesium hydroxide and aluminium hydroxide can act as antacids.
(a) Write an equation for the reaction of hydrochloric acid with each of these antacids.
(b) Identify which antacid neutralizes the greater amount of acid if 0.1 mol of each antacid is used.
(c) Explain why potassium hydroxide is not used as an antacid.
15 (a) 100 cm3 of a buffer is prepared which contains 0.100 mol dm−3 butanoic acid and 0.200 mol
dm−3 sodium butanoate. What is the pH of this buffer? The pKa of butanoic acid is 4.82.
(b) How would the pH of the buffer alter if 20 cm3 of distilled water was added to the original
solution?
D.5
Antiviral medications
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.
●●
●●
Guidance
Structures for oseltamivir and zanamivir can be found in the IB data booklet in section 37.
Viruses: nature’s most successful parasites
Figure 15.22 shows that viruses come in different shapes and sizes and are all
extremely small. Their diameters range from 20 to 300 nm, which means that they are
sub-microscopic. In other words they cannot be studied with a light microscope, but
only with an electron microscope.
594
Viruses are such small and simple structures that there is debate about whether
Figure 15.22
viruses.
they can be classified as living organisms in their own right. They contain only two
main components, protein and nucleic acid (either RNA or DNA), have no cellular
structure, and are only capable
HIV virus with its lipid envelope
T4 bacteriophage
of reproducing inside another
DNA
living cell. In all these ways
they are different from bacteria,
protein coat
which have a complex cellular
structure and the ability
sheath
to survive and reproduce
baseplate
independently from other
tail fibre
living cells.
Viruses are in fact the original
hijackers – they literally take
over the functioning of another
cell, the so-called host cell, and
100 nm
use it to carry out their own
reproduction. The host cell’s
components are used in the assembly of new viral particles and in the process the cell
eventually dies, releasing thousands of viral particles into the organism. Viruses are
usually somewhat specific for their host, and different strains exist that infect bacteria,
plants, and animals.
The war against viruses
The body’s defence 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. Another
example is the chicken pox
virus that can cause the
different disease shingles
years after the original
infection.
Despite the body’s defences,
viral infections claim the
lives of millions of people
each year and are responsible
for an even greater number
of illnesses, many of them
serious. Diseases such as
measles, meningitis, and
polio are caused by viruses,
as are more recent diseases
Examples of
lipid envelope
viral proteins
incorporated in
envelope
viral RNA
core proteins
25 nm
The words virus and
infection have been
adopted in technological
jargon to describe a type
of malicious software that
inserts itself into computer
files and replicates,
usually causing harm to
the system. Does the use
of these terms depend
on a knowledge of their
biological origin? To
what extent is knowledge
implicit in language?
Artwork of a SARS virus
particle inside a cell. SARS
(severe acute respiratory
syndrome) is an often fatal
lung disease that first appeared
in China in late 2002 and
spread rapidly through the
world via air travel. The virus
is related to the type that
causes the common cold. Like
all viruses it cannot replicate
by itself but instead uses the
machinery of the host cell to
produce more copies of itself.
Antibiotics are effective
against bacteria but not
against viruses.
595
15
Polio is a highly infectious
disease caused by a virus
which invades the nervous
system. It most commonly
affects children under five
years old, leaving many
who survived crippled
and paralysed. There is
no cure, but there are
effective vaccines, which
have been available since
the 1950s. Immunization
programmes have
eradicated polio from
most of the world, but the
disease is still endemic in
Afghanistan, Nigeria, and
Pakistan. The Global Polio
Eradication Initiative was
launched in 1988 and
tracks all new cases on a
weekly basis. Its goal is to
eradicate polio worldwide
by immunizing every child
until transmission stops.
Option D: Medicinal chemistry
such as AIDS, ebola, and avian flu. The development of effective treatments against
viruses is therefore one of the most pressing challenges of modern medicine.
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. This is why antibiotics are not effective
against viruses. In a sense viruses are so stripped-down structurally that there is little
for a drug to target.
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.
There have, though, been successes in the treatment of viral infections. 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
programmes have reduced the incidence of diseases such as cholera, polio, and
measles. In 1980 the World Health Organization declared that smallpox has been
eradicated from all parts of the world.
NATURE OF SCIENCE
Edward Jenner (1749–1823) pioneered the work that eventually led to the global eradication
of the devastating disease smallpox. Yet his methods would not stand the test of today’s ethical
standards for scientific experimentation. Jenner observed that people who suffered from the
relatively mild disease cowpox did not seem to contract smallpox (a more serious disease).
He tested his theory on an eight-year-old boy by first injecting him with pus from a cowpox
pustule, and when the boy had recovered from cowpox, injected him with pus from a smallpox
pustule. The boy did not develop smallpox. When he was told he needed more proof, Jenner
repeated the practice on more children, including his own baby son. Despite the evidence,
Jenner’s work was slow to be accepted as many people found the idea of innoculating the
body with disease to be repulsive. But eventually the results spoke for themselves, and the use
of vaccination became widespread.
The word vaccine is
derived from the Latin
word vacca for cow. It
was first used by Edward
Jenner in 1798 in the
context of his work on
cowpox and smallpox.
Jenner used intuition and careful observation to design a process that he believed would
be beneficial to others. Consider other cases where scientists may have had to balance the
courage of their convictions with contrary public perception.
Mutations in a virus can, however, limit the effectiveness of some vaccines. For example,
flu vaccines are useful only against the known strains, and as these change through
mutation, different vaccines usually have to be prepared and administered every year.
The main strategy to treat viral infections is the administration of specific medicines
known as antivirals. These all interfere in some way with the viral life cycle and so
prevent the release of new viral particles from the cell. Some antivirals work by altering
the cell’s DNA, its genetic material, so that the virus cannot use it to multiply. Others
block enzyme activity within the host cell which prevents the virus from reproducing.
One reasonably effective antiviral drug is Amantadine which has a cage like structure
and causes changes in the cell membrane that prevent the entry of a virus into the host
cell. It is therefore best used as a prophylactic treatment or given before the infection
has spread widely – a difficult task given the speed at which infections can strike.
Some recent advances in the development of antivirals for the flu virus are discussed in
the next section.
596
Flu viruses: a case study in antivirals
Influenza, commonly known as the flu, is such a common disease that most of us
can expect to experience it during our lives. Its symptoms include chills, headache,
sore throat, and weakness, but it can develop into much more serious illnesses such
as pneumonia. Flu infections can be particularly serious in the elderly and those with
compromised immune systems. It is estimated that about half a million people die of
flu every year, and there are constant fears of a global outbreak, known as a pandemic.
In November 1918, the same month in which World War I ended, a flu pandemic started in
which 20 million people died in less than 2 years. It is believed that the outbreak started with
a relatively harmless strain of flu that slowly evolved into a very virulent strain. Its effects were
global, with large numbers of casualties in the Pacific region, Africa, and North America. It is
considered to be the worst pandemic of all time, often referred to as the ‘Spanish flu’.
Flu is caused by two main types
of virus known as 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.
1
2
Hemagglutinin (H) is a
glycoprotein that enables the
viral particle to ‘dock’ with
the host cell before it enters.
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.
Computer artwork of the
action of an antiviral drug,
shown in blue, blocking an ion
channel in the viral surface.
This prevents the release of the
viral genetic material into the
host cell, and so interrupts the
viral replication and infection
cycle. Viral surface proteins are
shown in red and yellow in the
background.
Cut-away computer artwork
of an influenza virus particle.
The surface shows two
types of protein spike,
hemagglutinin shown in red,
and neuraminidase (shown in
yellow). These determine the
strain of virus and are essential
to its life cycle. Other viral
proteins are shown in purple,
and the genetic material, RNA,
is shown in yellow in the core.
These two molecules come in a variety of subunits which control the infectivity of the
virus. The naming system of viruses such as H1N1 and H5N1, refers to the different
forms of these molecules that are present.
In 2009 a new strain of the influenza A virus, known as H1N1, was identified as causing flu
infections. As people had little natural immunity to this strain, the infection spread globally
causing serious illness and death, and the World Health Organization (WHO) declared it a
pandemic. The alert was lifted in 2010 when the number of infections had declined steeply.
Debate continues on whether the pandemic designation was an exaggerated response,
possibly triggered by economic interests in increased sales of vaccines and antivirals. It is
believed that more than 250 000 people died of the disease, mostly in Africa and South-East
Asia.
597
15
Figure 15.23 Summary
of the life cycle of the flu
virus showing the roles
of hemagglutinin and
neuraminidase.
It may be of help to you
to learn a little bit more
about enzymes – read
pages 468–473 in the
Biochemistry option
chapter.
Option D: Medicinal chemistry
sialic
acids
binding via
hemagglutinin
hemagglutinin
virus
multiplication
of virus in cell
neuraminidase
release via
neuraminidase
The action of hemagglutinin
and neuraminidase is shown
in Figure 15.23.
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.
As an enzyme,
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 fit with the enzyme.
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.
oseltamivir (Tamiflu)
and zanamivir (Relenza)
are both neuraminidase
inhibitors that prevent
the release of new viral
particles from infected
cells.
Molecular model of the
neuraminidase enzyme found
on the surface of the influenza
virus, in a complex with the
drug oseltamivir. Binding of
the drug at the enzyme’s active
site inhibits its action, and so
prevents the release of new
viral particles from the host
cell.
598
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 (Tamiflu). As can be seen in Figure 15.24
and the table on page 599, both drugs have a chemical structure similar to sialic acid
and so are able to bind at the active site in neuraminidase. This class of drug is active
against both influenza A and B viruses. Tamiflu and Relenza are claimed to reduce the
symptoms of flu and shorten the time of its effects, but must be taken within 48 hours
of the appearance of symptoms.
HO
Figure 15.24 The structure of
the neuraminidase substrate
sialic acid, showing the
similarity of its structure to that
of the inhibitors oseltamivir
and zanamivir.
COOH
C
O
OH
H2C
OH
H
C
C
H
OH
HN
OH
ChAlleNge
youRSelF
C
H3C
O
3 Suggest why neuraminidase
inhibitors can be described
as competitive inhibitors.
The table below compares and contrasts the two drugs Tamiflu and Relenza.
Oseltamivir (Tamiflu)
Zanamivir (Relenza)
Structure
H3C
C2H5
HC
H5C2
OH
NH
O
H5C2
H3C
O
C
NH2
O
C
H2C
H
C
OH
OH
C
O
NH
C
N
H O
C
NH2
NH2
COOH
O
Functional groups
alkenyl
ether
primary amino
carboxyamide
ester
alkenyl
ether
primary amino
carboxyamide
carboxylic acid
hydroxyl (3)
Drug action
neuraminidase inhibitor
neuraminidase inhibitor
Administration
orally
inhalation
Resistance to drug
some rare strains of flu virus have shown
resistance
no resistance reported
Counter-effects
nausea, vomiting
possible asthma
Antiretroviral drugs are expensive and so have been very poorly distributed in the countries
where they are generally needed the most. The Clinton Health Access Initiative Foundation
(CHAI) began as a campaign to address the HIV/AIDS crisis in the developing world and
strengthen health systems there. A major achievement is that nearly six million people now
have access to HIV medications at costs reduced to about $200 per person per year. This
includes a large number of HIV-positive children who were previously left untreated. It is
estimated that one child dies every two minutes from mother to child transmission of HIV,
and global efforts are focused on preventing this, especially in Cambodia, Ethiopia, Lesotho,
Malawi, Tanzania, and Vietnam.
The structures of
oseltamivir and zanamivir
are given in section 37 of
the IB data booklet.
599
15
Option D: Medicinal chemistry
NATURE OF SCIENCE
In many countries pharmaceutical companies are not under a legal obligation to publish all
available data about drugs. It is estimated that up to half of all drug trial data have not been
shared. This lack of transparency is a source of controversy and concern to doctors, patients,
and researchers, and has led to pressure from watchdog organizations and regulators to
compel drug companies to release all of their data.
Computer artwork of HIV
replication. The viral particles,
shown in green, surround the
white blood cell, shown in
blue, and attach to its surface
using specific proteins for
recognition. Viral RNA, shown
in pink, is then injected into
the cell and using reverse
transcriptase synthesizes DNA
which integrates into the host’s
chromosome. This can be
seen in the white cell nucleus
in the centre. New viral
particles are assembled within
the cell and are shown at the
bottom budding from the cell,
taking part of the membrane
as an envelope.
AIDS: a viral pandemic
The condition known as AIDS, acquired immune deficiency syndrome, caused by
the human immunodeficiency virus (HIV), was first diagnosed in humans in 1981.
The infection is transmitted from person to person through sexual or parenteral
exposure to fluids such as blood, semen, and mucus that contain HIV. The disease
AIDS is characterized by a failure of the immune system, so that the body falls prey
to life-threatening opportunistic infections such as pneumonia and forms of cancer.
The infection has spread at an alarming rate through the global population and it is
estimated that approximately 33 million people are currently HIV positive, with a
likelihood of developing AIDS. Although cases have been reported in all regions of
the world, a very high proportion of people who are HIV positive live in sub-Saharan
Africa.
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.
The fight against HIV infection
There are three main reasons why HIV is
proving even more challenging than other
viruses to defeat.
2
3
600
1 The virus destroys helper T cells, the very
cells in the immune system that should
be defending the body against the virus.
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.
The virus often lies dormant within host cells, so the immune system has nothing
to respond to.
Despite the challenges, great progress has been made in the development of specific
antivirals for HIV infection. The drugs are known as antiretroviral drugs, ARVs,
and about 20 of these are now commonly available. Although these drugs do not cure
the patient, they can give lasting suppression of the HIV infection. This means that
with appropriate treatments, HIV infection can be considered as a potentially chronic
disease rather than as a fatal disease. Antiretroviral treatment during pregnancy can
also effectively prevent transmission of the disease from mother to child.
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.
Of these targets, inhibitors of the
viral enzyme reverse transcriptase
are the most widespread, and 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. The cost for
most combination treatments is
approximately $12 000 per patient per
year.
The development of ARVs is a field
which is advancing rapidly as more
drugs become available. Medical
doctors must consider how to tailor a
prescription to individual patients, who
may benefit from different regimens of
different drugs. Considerations of sideeffects, potency, expense, convenience,
and prevention of transmission must all be weighed. ARV treatments generally need to
be sustained throughout life.
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 HIV-negative 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.
Molecular model of the HIV
enzyme reverse transcriptase
complexed with the inhibitor
efavirenz. Binding of the
inhibitor to the enzyme
prevents HIV reproducing
in the host cell. Efavirenz
is therefore an effective
antiretroviral drug that reduces
the spread of HIV infection.
601
15
Option D: Medicinal chemistry
NATURE OF SCIENCE
The development of effective antivirals is a good example of the interdiscipinary nature of
many scientific endeavours. Technological advances in the areas of electron microscopy and
X-ray crystallography have provided insights into structures that could not otherwise be known.
Advances in molecular biology have helped explain the role of viral proteins and genetic
material in the viral life cycle. This cumulative knowledge has helped to drive research in the
pharmaceutical industry, resulting in the availability of effective new drugs for many diseases. At
best, science is a collaborative process in which findings from different disciplines contribute to
the achievement of a common goal.
Exercises
16 Why are viral infections not able to be treated with antibiotics?
17 With reference to the structure of the influenza virus, explain why it is possible to suffer from flu several
times during a lifetime.
18 Explain why the antivirals Tamiflu and Relenza must be taken within a very short time after the
appearance of the symptoms of flu.
19 Discuss some of the challenges and successes in the global response to the AIDS pandemic.
D.6
Environmental impact of some
medications
Understandings:
High-level waste (HLW) is waste that gives off large amounts of ionizing radiation for a long time.
Low-level waste (LLW) is waste that gives off small amounts of ionizing radiation for a short time.
●● Antibiotic resistance occurs when microorganisms become resistant to antibacterials.
●●
●●
Applications and skills:
Description of the environmental impact of medical nuclear waste disposal.
Discussion of environmental issues related to left-over solvents.
●● Explanation of the dangers of antibiotic waste, from improper drug disposal and animal waste, and
the development of antibiotic resistance.
●● Discussion of the basics of Green Chemistry (sustainable chemistry) processes.
●● Explanation of how Green Chemistry was used to develop the precursor for Tamiflu (oseltamivir).
●●
●●
Guidance
The structure of oseltamivir is provided in the data booklet in section 37.
In this chapter we have explored many of the ways in which modern medicine has
made significant contributions to advances in human health. Better diagnosis and
treatments of many conditions have led to improvements in the quality of life, and
increases in longevity in many parts of the world.
602
A recurring theme has been an awareness of how side-effects of medications may
directly impact health. Consequently, side-effects to the patient are monitored and
negative effects avoided wherever possible. In a parallel way, the activities of the
pharmaceutical industry in drug preparation, administration, and disposal produce
side-effects in the environment. Many of these are negative and potentially damaging
to human health. It is thus equally important that these environmental side-effects
are monitored, with policies and procedures put in place to minimize their negative
impact. Failure to do so would be self-defeating, as the quality of the environment is
critical to the health of all living things.