Rational drug development remains an inexact science. The success and failure
of drugs is often attributed to interesting chemical rationalizations but, individually,
such explanations have had
disappointing predictive value in pharmacology. Faithful, disciplined application
of chemical principles to increasingly sophisticated understanding of biology
can lead to new drug candidates and can help reveal new principles in biology.The
value and power of chemical biology is best appreciated in the context of understanding
and curing diseases.Malaria is a major cause of morbidity and mortality in the
world. With the emergence of resistance against traditional drugs, there is
an urgent need for new, affordable medicines against Plasmodium.Current research
focuses on four areas.
(i) Cellular control mechanisms influence drug selectivity. Some malarial drug
targets may be uniquely sensitive to inhibitors in part due to tight RNA-protein
interactions. Such autoregulation in malaria is different from what is seen
in the host.
(ii) Drug resistance in malaria emerges from parasite populations with mutator-like
phenotypes. We are developing a more detailed model for this phenotype and identifying
the molecular players involved in the process.
(iii) Good drug targets are attacked in multiple ways. Thymidylate synthesis
in malaria can be targeted with high selectivity by starting with appropriate
pro-drugs, by supplementing non-selective antifolates with rescuing nutrients
that only the host can use, and by disrupting unique protein-protein interactions.
(iv) Genomics tools for malaria. In collaborations with Stanford, UCSF, and
NIH, we are developing microarrays for malaria. Current efforts are also directed
at applying QTL mapping techniques to expression patterns in malaria, at developing
robust negative selection systems for malaria, anddeveloping a genome-wide library
of ligands for malaria.