Biomedical Engineering Reference
In-Depth Information
three diseases listed are responsible for the deaths of millions of people each
year, many of them children. The lack of modern sanitation and health-care
systems exacerbates the problems caused by these infections. Several additional
aspects make these diseases increasingly problematic for global health: first,
because of the devastating effects of HIV infection on the human immune
system, many individuals are susceptible to co-infection with the other two
agents. Thus, co-infections of HIV and malaria or HIV and tuberculosis are
observed in the majority of individuals. In fact, the major cause of death at this
time for HIV-1-positive individuals is tuberculosis.
The second aspect for concern is that the drugs that have been developed and
used over the past 50 years to fight malaria are becoming increasingly useless
due to the development and spread of drug-resistant variants.
1,2
Drug-resistant
tuberculosis has already reached the developed countries of the world, and only
the limited range of the carrier of malaria, the Anopheles mosquito, limits the
spread of that organism to the tropical areas. However, malaria can still affect
travelers to the tropics, and many cases of 'airport malaria' have been observed
where returning vacationers bring back the infection to their home towns and
pass it on to people in the local area for a brief time. In addition to tourists,
military personnel, diplomats, and those conducting business in the increas-
ingly global economy are subject to infection.
Efforts to develop vaccines against malaria have been under way for some
time, but many barriers have developed. Nonetheless, these studies must con-
tinue, as they would provide the ultimate weapon against malaria.
For all these reasons, the development of new compounds that will kill the
malaria parasite is an important objective of current research. However, given
the fact that most individuals who live in the tropical regions are poor and are
not able to afford expensive medicine, efforts should be made to develop
inexpensive approaches to drug development. This will take many years to
achieve, and in the interim it is necessary to employ traditional methods of drug
discovery including synthesis of sets of compounds as is done in medicinal
chemistry laboratories, biochemical and structure-based methods to learn
about the active site preferences of key enzymes in the parasites life cycle, and
studies of the biological role of the proteins of the parasite.
The global battle against AIDS has provided an outstanding precedent for
the use of protease inhibitors as an anti-infective strategy. After the cloning and
initial characterization of HIV-1 protease, drug discovery proceeded, based on
the development of peptidomimetic compounds. These resemble peptide sub-
strates but have a non-hydrolyzable bond at the point of normal cleavage.
These, in turn, were based on earlier work on inhibitors of renin, another
aspartic proteinase. With over 30 years of drug-discovery background for the
aspartic peptidases, the knowledge that this enzyme family was critical to the
malaria-parasite life cycle was rapidly followed by studies of peptidomimetic
compounds based on peptide substrates. In addition, however, natural pro-
ducts provide many compounds with promising antimalarial activity. Because
nature could provide low-cost drug alternatives, it is important that these leads
be followed up.
