Biomedical Engineering Reference
In-Depth Information
FIGURE 17.7
Time line for antimalarials with a new mechanism of action [40
−
43].
particularly as combination therapies with different targets are being used increasingly
to lessen the rate of resistance. Recent efforts to uncover new antimalarial chemotypes
[35] include large screening efforts involving up to 2 million compounds from GSK's
screening collection [36]. This has produced some promising leads that have been
developed [37,38], but none has yet progressed to the clinic. Given a generalized
assumption that compounds with similar structures share a similar mode of action
(the similarity principle) [39], if our goal is to produce antimalarials with new modes
of action, diversity-oriented synthesis (DOS) can be an important strategy in the fight
against this disease. In this section we highlight two examples of ways in which DOS
is addressing needs in this area.
In 2010, Novartis reported a screening campaign of just 10,000 diverse compounds
together with 2000 natural products, which found promising new antimalarial agents
[44]. This study was a collaboration of the Novartis Institute for Tropical Diseases,
the Genomics Institute of the Novartis Research Foundation (GNF), the Biomedical
Primate Research Centre, and the Swiss Tropical Institute. The goal of this program
was to develop antimalarials with new mechanisms of action, and their strategy
incorporated diverse compounds, with new chemotypes, tested in phenotypic assays
where no assumptions on the most relevant protein targets were made. Specifically, the
GNF developed a high-throughput
P. falciparum
assay which enabled the screening of
