Biomedical Engineering Reference
In-Depth Information
Figure 11.5
This figure shows a model of Plasmodium falciparum plasmepsin V
(Guruprasad et al.
72
). This enzyme has not been crystallized, but the
sequence identity with other members of the family has permitted con-
struction of a homology-based model. At three points in the sequence,
Guruprasad et al. left out the inserts in the sequence that are most likely
responsible for targeting of the protein to its location in the endoplasmic
reticulum of the parasite, where it plays a role in the process of secretion
of parasite proteins into the erythrocyte host.
In order to make the strongest and most effective drug for therapy of malaria
infection, it will be necessary to optimize the binding of compounds to the most
critical enzyme in the parasite. As described in the preceding section, a clear
biological role for plasmepsin V has been determined, and inhibitor develop-
ment will move forward with that enzyme as a target. However, if compounds
are developed that bind strongly to plasmepsin V without consideration of their
binding to the other six plasmepsins known to exist in the parasite during the
intraerythrocytic stage of its life cycle, it is possible that a drug candidate could
be less effective than hoped due to binding to the other plasmepsins. In other
words, the effective dose of a drug could be reduced due to binding to off-target
proteins, especially to related enzymes such as other plasmepsins. As there are
similarities in the structures of the plasmepsins that have been studied by X-ray
crystallography, and as it has been possible to model the structure of plas-
mepsin V, IX, and X by using the aspartic proteinase fold, it is reasonable to
expect that drugs will bind to all members of this family.
11.5 Inhibitor Development
This section will describe some studies of inhibitor development targeted
against the plasmepsins. It will not be comprehensive, as there are hundreds of
