cells against viral infection by altering the plasma membrane (i.e., in a nonspecific manner).
It also activates an endonuclease that destroys viral mRNA and a protein kinase that
inactivates a protein synthesis initiation factor. Interferon can be isolated very laboriously
from leukocytes and other cells, but the gene that encodes its synthesishas been transferred
into bacteria by recombinant DNA techniques. Recently,α-interferonhas been suggested
as a possible therapy for SARS.
9.3.4 Antiviral Design: Evolving TargetsViruses are important pathogens in human disease. The possibility of a worldwide
“viral flu” pandemic that kills 50 million people is a haunting spectre. The need
for new and effective antivirals is undeniable. Accordingly, new avenues of antiviral drug
design are being pursued. Classes of agents known as fusion inhibitors are being devised.
A fusion protein is a viral membrane protein that interacts with lipids to induce fusion
during viral entry into the host cell. Various classes of fusion proteins are recognized;
some have had their three-dimensional structures evaluated by crystallographic studies.
In addition to fusion inhibitors, novel viral enzymes (e.g., integrase) are also being
studied; integrase inhibitors may constitute a new direction in antiviral therapy. Viral serine
proteases have likewise been identified as attractive antiviral targets. Based upon crys-
tallographic structural data, novel peptidomimetic inhibitors are being developed.
9.4 Drug Design Targeting Bacteria
Traditionally, biologists endeavored to categorize all organisms into two kingdoms:
plant or animal. Realizing that this broad generalization could not apply to all species,
Haeckel proposed in 1866 that microorganisms be placed in a separate kingdom, the
Protista. The Protista were further subdivided into prokaryotes andeukaryotes.
Eukaryotes (protozoa, fungi, molds) are more advanced, having their genetic mater-
ial in a nucleus that is separated from the rest of the cell by a nuclear membrane;
prokaryotes (bacteria, blue-green algae) are more primitive and are characterized
by having their genetic material in the form of simple filaments of DNA that are
not separated from the cytoplasm by a membrane. Bacteria are differentiated from
other prokaryotes by the fact that they do not have chlorophyll for purposes of
photosynthesis.
Bacteria have been killing humans for millennia. Many diseases (pneumonia, menin-
gitis, gangrene) are caused by bacterial infections. One of the greatest triumphs of med-
icinal chemistry in the 20th century was the discovery of antibacterial drugs. There are
many types of bacteria that can produce disease in humans. Although they can be
classified using rigid biological nomenclature systems, this is not always clinically
relevant. Accordingly, a somewhat more commonly employed classification system is
as follows:
- Gram-negative enteric bacteria (infectious diarrhea)
Pseudomonas
Salmonellae
Shigellae
Vibrios
EXOGENOUS PATHOGENS AND TOXINS 559