Comparative chemical genomics reveal that the spiroindolone antimalarial KAE609 (Cipargamin) is a P-type ATPase inhibitor
Year: 2016
Type: article
Abstract: The spiroindolones, a new class of antimalarial medicines discovered in a cellular screen, are rendered less active by mutations in a parasite P-type ATPase, PfATP4. We show here that S. cerevisiae also acquires mutations in a gene encoding a P-type ATPase (ScPMA1) after exposure to spiroindolones and that these mutations are sufficient for resistance. KAE609 resistance mutations in ScPMA1 do not confer resistance to unrelated antimicrobials, but do confer cross sensitivity to the alkyl-lysophospholipid edelfosine, which is known to displace ScPma1p from the plasma membrane. Using an in vitro cell-free assay, we demonstrate that KAE609 directly inhibits ScPma1p ATPase activity. KAE609 also increases cytoplasmic hydrogen ion concentrations in yeast cells. Computer docking into a ScPma1p homology model identifies a binding mode that supports genetic resistance determinants and in vitro experimental structure-activity relationships in both P. falciparum and S. cerevisiae. This model also suggests a shared binding site with the dihydroisoquinolones antimalarials. Our data support a model in which KAE609 exerts its antimalarial activity by directly interfering with P-type ATPase activity.
Source: Scientific Reports
DOI: 10.1038/srep27806
Authors: Gregory M. Goldgof, Jacob D. Durrant, Sabine Ottilie, Edgar Vigil, Kenneth E. Allen, Felicia Gunawan, Maxim Kostylev, Kiersten A. Henderson, Jennifer Yang, Jake Schenken, Gregory M. LaMonte, Micah J. Manary, Ayako Murao, Marie Nachon, Rebecca Murray, Maximo Prescott, Case W. McNamara, Carolyn W. Slayman, Rommie E. Amaro, Yo Suzuki, Elizabeth A. Winzeler
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,690
Funders: Bill and Melinda Gates Foundation, National Institutes of Health, University of California, San Diego, National Defense Science and Engineering Graduate, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Center for Advancing Translational Sciences, Air Force Office of Scientific Research
Awards: G1042587991, G1070450565, G1110505228, G1137917714, G1313421729, G145338696, G205123881, G214752006, G2714352180, G297113894, A Structural Systems Biology Approach to Drug Discovery, University of California San Diego - to identify the mechanism of action of candidate antimalarial chemical compounds, so that they can be turned into new effective and inexpensive dru..., G598865872, G7791925507, Specialized Cancer Center Support Grant, University of California San Diego - To enable the design of effective combinations of next-generation anti-malarials for overcoming drug resistance by classifying anti-malarial drug c..., G9000002805, G9000034035, G9000048997, G9000051603, G9000078300, G9000093893, G9000131164, G9000158104, G9000184705, G9000322804
OpenAlex ID: W2423805083