polar substituent groups to influence drug solubility and absorption can be manipulated
under such circumstances to reduce the likelihood of drug absorption.
9.1.3 Microbial Genomics and Drug Design
As discussed in chapter 3, the elucidation of both the human genome and numerous
pathogen genomes may exert a profound impact on the understanding and treatment of
human disease. When designing drugs to contend with exogenous pathogens such as
infectious microbes, it is immensely useful to understand the biochemistry of the
microbe and how that biochemistry differs from human biochemistry. Such data are
useful when designing a drug to kill a microbe without harming the human host.
Understanding the genome of a microorganism enables insights concerning its biochemical operation and the identification of a potential druggable target; comparing the
microbe’s genome to that of a human enables an appreciation of whether that target is
shared between the microbe and humans.
Over the past 5–10 years, a number of pathogenic microbial genomes have been
determined. Amongst these, one of the most noteworthy has been the full genome of
Plasmodium falciparum, the most important of the parasites causing malaria. This parasite’s 30-million-base-pair genome is spread over 14 chromosomes. The elucidation
of this genome was challenging because adenine and thymine, two of the four building blocks of DNA, together make up more than 80% of the organism’s genome.
Sifting through this enormous collection of genomic data on Plasmodium falciparum
and comparing it to the human genome for purposes of rational drug design is a
Herculean task, made somewhat easier by recent advances in bioinformatics (discussed
in chapter 1).
The use of a variety of techniques, ranging from classical drug design to genomebased drug design, will be required for a full and effective attack on the microbes of
human disease, extending from simple prions to complex parasites.
9.2 DRUG DESIGN TARGETING PRIONS
Prion diseases have attracted immense attention over the past decade, prompted, in part,
by the outbreak of “mad cow disease” in the United Kingdom. The most common prion
disease is sporadic Creutzfeldt–Jakob disease (CJD). Clinically, CJD is characterized
by a rapidly progressive dementia accompanied variably by early-onset seizures,
insomnia, disordered movements, and psychiatric disturbances; the disease is uniformly
fatal. Histochemically, the principal pathological feature of prion disease is the abnormal accumulation of an amyloid-like material composed of prion protein (PrP), which
is encoded by a single gene on the short arm of chromosome 20.
The abnormal deposits found in the brains of CJD victims consist of an abnormal isoform of PrP. Prion protein is normally found in cells. Detailed structural studies show
that normal cellular PrP (PrP
C
) is a soluble protein whose conformation is rich in
α-helices with very little β-sheet. The PrP protein extracted from the brains of CJD
victims (i.e., PrP
SC
) is identical in primary amino acid sequence to the normal PrP (PrP
C
).
However, PrP
SC has a much greater content of β-sheet conformation with little α-helical
structure. Thus PrP
SC is neurotoxic because of its three-dimensional structure. When the
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MEDICINAL CHEMISTRY
under such circumstances to reduce the likelihood of drug absorption.
9.1.3 Microbial Genomics and Drug Design
As discussed in chapter 3, the elucidation of both the human genome and numerous
pathogen genomes may exert a profound impact on the understanding and treatment of
human disease. When designing drugs to contend with exogenous pathogens such as
infectious microbes, it is immensely useful to understand the biochemistry of the
microbe and how that biochemistry differs from human biochemistry. Such data are
useful when designing a drug to kill a microbe without harming the human host.
Understanding the genome of a microorganism enables insights concerning its biochemical operation and the identification of a potential druggable target; comparing the
microbe’s genome to that of a human enables an appreciation of whether that target is
shared between the microbe and humans.
Over the past 5–10 years, a number of pathogenic microbial genomes have been
determined. Amongst these, one of the most noteworthy has been the full genome of
Plasmodium falciparum, the most important of the parasites causing malaria. This parasite’s 30-million-base-pair genome is spread over 14 chromosomes. The elucidation
of this genome was challenging because adenine and thymine, two of the four building blocks of DNA, together make up more than 80% of the organism’s genome.
Sifting through this enormous collection of genomic data on Plasmodium falciparum
and comparing it to the human genome for purposes of rational drug design is a
Herculean task, made somewhat easier by recent advances in bioinformatics (discussed
in chapter 1).
The use of a variety of techniques, ranging from classical drug design to genomebased drug design, will be required for a full and effective attack on the microbes of
human disease, extending from simple prions to complex parasites.
9.2 DRUG DESIGN TARGETING PRIONS
Prion diseases have attracted immense attention over the past decade, prompted, in part,
by the outbreak of “mad cow disease” in the United Kingdom. The most common prion
disease is sporadic Creutzfeldt–Jakob disease (CJD). Clinically, CJD is characterized
by a rapidly progressive dementia accompanied variably by early-onset seizures,
insomnia, disordered movements, and psychiatric disturbances; the disease is uniformly
fatal. Histochemically, the principal pathological feature of prion disease is the abnormal accumulation of an amyloid-like material composed of prion protein (PrP), which
is encoded by a single gene on the short arm of chromosome 20.
The abnormal deposits found in the brains of CJD victims consist of an abnormal isoform of PrP. Prion protein is normally found in cells. Detailed structural studies show
that normal cellular PrP (PrP
C
) is a soluble protein whose conformation is rich in
α-helices with very little β-sheet. The PrP protein extracted from the brains of CJD
victims (i.e., PrP
SC
) is identical in primary amino acid sequence to the normal PrP (PrP
C
).
However, PrP
SC has a much greater content of β-sheet conformation with little α-helical
structure. Thus PrP
SC is neurotoxic because of its three-dimensional structure. When the
546
MEDICINAL CHEMISTRY