TY - JOUR
T1 - Searching for new antimalarial therapeutics amongst known drugs
AU - Weisman, Jennifer L.
AU - Liou, Ally P.
AU - Shelat, Anang A.
AU - Cohen, Fred E.
AU - Guy, R. Kiplin
AU - DeRisi, Joseph L.
PY - 2006/6
Y1 - 2006/6
N2 - The need to discover and develop new antimalarial therapeutics is overwhelming. The annual mortality attributed to malaria, currently approximately 2.5 million, is increasing due primarily to widespread resistance to currently used drugs. One strategy to identify new treatment alternatives for malaria is to examine libraries of diverse compounds for the possible identification of novel scaffolds. Beginning with libraries of drug or drug-like compounds is an ideal starting point because, in the case of approved drugs, substantial pharmacokinetic and toxicologic data should be available for each compound series. We have employed a high-throughput screen of the MicroSource Spectrum and Killer Collections, a library of known drugs, bioactive compounds, and natural products. Our screening assay identifies compounds that inhibit growth of Plasmodium falciparum cultured in human erythrocytes. We have identified 36 novel inhibitors of P. falciparum, of which 19 are therapeutics, and five of these drugs exhibit effective 50% inhibitory concentrations within similar ranges to therapeutic serum concentrations for their recently indicated uses: propafenone, thioridazine, chlorprothixene, perhexiline, and azlocillin. The findings we report here indicate that this is an effective strategy to identify novel scaffolds and therefore aid in antimalarial drug discovery efforts.
AB - The need to discover and develop new antimalarial therapeutics is overwhelming. The annual mortality attributed to malaria, currently approximately 2.5 million, is increasing due primarily to widespread resistance to currently used drugs. One strategy to identify new treatment alternatives for malaria is to examine libraries of diverse compounds for the possible identification of novel scaffolds. Beginning with libraries of drug or drug-like compounds is an ideal starting point because, in the case of approved drugs, substantial pharmacokinetic and toxicologic data should be available for each compound series. We have employed a high-throughput screen of the MicroSource Spectrum and Killer Collections, a library of known drugs, bioactive compounds, and natural products. Our screening assay identifies compounds that inhibit growth of Plasmodium falciparum cultured in human erythrocytes. We have identified 36 novel inhibitors of P. falciparum, of which 19 are therapeutics, and five of these drugs exhibit effective 50% inhibitory concentrations within similar ranges to therapeutic serum concentrations for their recently indicated uses: propafenone, thioridazine, chlorprothixene, perhexiline, and azlocillin. The findings we report here indicate that this is an effective strategy to identify novel scaffolds and therefore aid in antimalarial drug discovery efforts.
KW - Biologic screening
KW - Drug discovery
KW - Malaria
UR - http://www.scopus.com/inward/record.url?scp=33746169858&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33746169858&partnerID=8YFLogxK
U2 - 10.1111/j.1747-0285.2006.00391.x
DO - 10.1111/j.1747-0285.2006.00391.x
M3 - Article
C2 - 16882315
AN - SCOPUS:33746169858
SN - 1747-0277
VL - 67
SP - 409
EP - 416
JO - Chemical Biology and Drug Design
JF - Chemical Biology and Drug Design
IS - 6
ER -