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Development of Toxoplasma gondii calcium-dependent protein kinase 1 (TgCDPK1) inhibitors with potent anti-toxoplasma activity.
| Title | Development of Toxoplasma gondii calcium-dependent protein kinase 1 (TgCDPK1) inhibitors with potent anti-toxoplasma activity. |
| Publication Type | Journal Article |
| Year of Publication | 2012 |
| Authors | Johnson, SM, Murphy, RC, Geiger, JA, DeRocher, AE, Zhang, Z, Ojo, KK, Larson, ET, Perera, GBK, Dale, EJ, He, P, Reid, MC, Fox, AMW, Mueller, NR, Merritt, EA, Fan, E, Parsons, M, Van Voorhis, WC, Maly, DJ |
| Journal | J Med Chem |
| Volume | 55 |
| Issue | 5 |
| Pagination | 2416-26 |
| Date Published | 2012 Mar 8 |
| ISSN | 1520-4804 |
| Keywords | Cell Line, Cell Proliferation, Coccidiostats, Crystallography, X-Ray, Drug Resistance, Enzyme Assays, Humans, Models, Molecular, Molecular Structure, Naphthalenes, Piperidines, Protein Kinase Inhibitors, Protein Kinases, Protozoan Proteins, Pyrazoles, Pyrimidines, Structure-Activity Relationship, Toxoplasma |
| Abstract | Toxoplasmosis is a disease of prominent health concern that is caused by the protozoan parasite Toxoplasma gondii. Proliferation of T. gondii is dependent on its ability to invade host cells, which is mediated in part by calcium-dependent protein kinase 1 (CDPK1). We have developed ATP competitive inhibitors of TgCDPK1 that block invasion of parasites into host cells, preventing their proliferation. The presence of a unique glycine gatekeeper residue in TgCDPK1 permits selective inhibition of the parasite enzyme over human kinases. These potent TgCDPK1 inhibitors do not inhibit the growth of human cell lines and represent promising candidates as toxoplasmosis therapeutics. |
| DOI | 10.1021/jm201713h |
| Alternate Journal | J. Med. Chem. |
| PubMed ID | 22320388 |
