Biomedical Engineering Reference
In-Depth Information
a new mechanism of action. Analysis of the resistant line genome relative to the
nonresistant parental reference line identified mutations in
pfatp4
, which is a cation
transporting P-type adenosine triphosphatase. While further work is necessary to
establish whether PfATP4 is the true target of NITD609 or part of a mechanism
to reduce its effectiveness, its identification suggests a departure from the known
mechanisms of action of the existing antimalarials. NITD609 is currently in phase
IIa clinical trials and would represent the first antimalarial with a novel mechanism
of action to progress to this stage in the last 20 years.
With the goals of creating a transformative screening collection, scientists at the
Broad Institute created a diverse library of
100,000 compounds using a DOS strat-
egy. Compounds in the Broad screening collection contain zero to three diversity sites
and up to five stereogenic centers. A full matrix of stereoisomers was synthesized,
giving rise to rich SSAR as well as SAR. In an attempt to discover novel antimalari-
als, a representative 8000-membered DOS “informer” subset of the larger screening
collection was screened using a whole-cell assay [48]. For each compound selected
to be in the screen, all possible stereoisomers were included. The assayed compounds
were selected computationally for maximum diversity, representing all libraries and
chemotypes in the overall collection. It was reasoned that compound selection in this
informer set would enable the rapid development of SSAR and SAR for the prioritiza-
tion and optimization of hit compounds. High-throughput screening of the compounds
at 5
>
M was conducted using a growth inhibition assay with multidrug-resistant Dd2
P. falciparum
parasites (Figure 17.10). Greater than 90% growth inhibition was seen
FIGURE 17.10
Summary of Broad Institute's HTS screening campaign.
