Pegoraro, S. et al. (2017) SC83288 is a clinical development candidate for the treatment of severe malaria. Nature Communications, 8, 14193. (doi: 10.1038/ncomms14193) (PMID:28139658) (PMCID:PMC5290327)
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Abstract
Severe malaria is a life-threatening complication of an infection with the protozoan parasite Plasmodium falciparum, which requires immediate treatment. Safety and efficacy concerns with currently used drugs accentuate the need for new chemotherapeutic options against severe malaria. Here we describe a medicinal chemistry program starting from amicarbalide that led to two compounds with optimized pharmacological and antiparasitic properties. SC81458 and the clinical development candidate, SC83288, are fast-acting compounds that can cure a P. falciparum infection in a humanized NOD/SCID mouse model system. Detailed preclinical pharmacokinetic and toxicological studies reveal no observable drawbacks. Ultra-deep sequencing of resistant parasites identifies the sarco/endoplasmic reticulum Ca(2+) transporting PfATP6 as a putative determinant of resistance to SC81458 and SC83288. Features, such as fast parasite killing, good safety margin, a potentially novel mode of action and a distinct chemotype support the clinical development of SC83288, as an intravenous application for the treatment of severe malaria.
| Item Type: | Articles |
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| Additional Information: | The research leading to these results has received funding from the Bundesministerium für Bildung und Forschung under the portfolio of the German Centre for Infectious Research (DZIF), the Wellcome Trust (grant number 098051), the Australian Research Council (grant number LP120200557), and the European Commission under the portfolio of the FP6-integrated project AntiMal (contract number LSHP-CT-2005-0188) and the 7th framework Center of Excellence EVIMalaR. Erratum: http://eprints.gla.ac.uk/203728/ |
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Otto, Professor Thomas |
| Authors: | Pegoraro, S., Duffey, M., Otto, T. D., Wang, Y., Rösemann, R., Baumgartner, R., Fehler, S. K., Lucantoni, L., Avery, V. M., Moreno-Sabater, A., Mazier, D., Vial, H. J., Strobl, S., Sanchez, C. P., and Lanzer, M. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Infection & Immunity |
| Journal Name: | Nature Communications |
| Publisher: | Nature Research |
| ISSN: | 2041-1723 |
| ISSN (Online): | 2041-1723 |
| Published Online: | 31 January 2017 |
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