BibTex format
@article{Schlott:2019:10.1016/j.chembiol.2019.03.015,
author = {Schlott, AC and Mayclin, S and Reers, AR and Coburn-Flynn, O and Bell, AS and Green, J and Knuepfer, E and Charter, D and Bonnert, R and Campo, B and Burrows, J and Lyons-Abbott, S and Staker, BL and Chung, C-W and Myler, PJ and Fidock, DA and Tate, EW and Holder, AA},
doi = {10.1016/j.chembiol.2019.03.015},
journal = {Cell Chemical Biology},
pages = {991--1000.e7},
title = {Structure-guided identification of resistance breaking antimalarial N-myristoyltransferase inhibitors},
url = {http://dx.doi.org/10.1016/j.chembiol.2019.03.015},
volume = {26},
year = {2019}
}
RIS format (EndNote, RefMan)
TY - JOUR
AB - The attachment of myristate to the N-terminal glycine of certain proteins is largely a co-translational modification catalyzed by N-myristoyltransferase (NMT), and involved in protein membrane-localization. Pathogen NMT is a validated therapeutic target in numerous infectious diseases including malaria. In Plasmodium falciparum, NMT substrates are important in essential processes including parasite gliding motility and host cell invasion. Here, we generated parasites resistant to a particular NMT inhibitor series and show that resistance in an in vitro parasite growth assay is mediated by a single amino acid substitution in the NMT substrate-binding pocket. The basis of resistance was validated and analyzed with a structure-guided approach using crystallography, in combination with enzyme activity, stability, and surface plasmon resonance assays, allowing identification of another inhibitor series unaffected by this substitution. We suggest that resistance studies incorporated early in the drug development process help selection of drug combinations to impede rapid evolution of parasite resistance.
AU - Schlott,AC
AU - Mayclin,S
AU - Reers,AR
AU - Coburn-Flynn,O
AU - Bell,AS
AU - Green,J
AU - Knuepfer,E
AU - Charter,D
AU - Bonnert,R
AU - Campo,B
AU - Burrows,J
AU - Lyons-Abbott,S
AU - Staker,BL
AU - Chung,C-W
AU - Myler,PJ
AU - Fidock,DA
AU - Tate,EW
AU - Holder,AA
DO - 10.1016/j.chembiol.2019.03.015
EP - 1000
PY - 2019///
SN - 2451-9448
SP - 991
TI - Structure-guided identification of resistance breaking antimalarial N-myristoyltransferase inhibitors
T2 - Cell Chemical Biology
UR - http://dx.doi.org/10.1016/j.chembiol.2019.03.015
UR - http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000476613500010&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
UR - https://www.sciencedirect.com/science/article/pii/S2451945619301114?via%3Dihub
UR - http://hdl.handle.net/10044/1/73974
VL - 26
ER -