TY - JOUR
T1 - Fast-Killing Tyrosine Amide ((S)-SW228703) with Blood- and Liver-Stage Antimalarial Activity Associated with the Cyclic Amine Resistance Locus (PfCARL)
AU - Imlay, Leah S.
AU - Lawong, Aloysus K.
AU - Gahalawat, Suraksha
AU - Kumar, Ashwani
AU - Xing, Chao
AU - Mittal, Nimisha
AU - Wittlin, Sergio
AU - Churchyard, Alisje
AU - Niederstrasser, Hanspeter
AU - Crespo-Fernandez, Benigno
AU - Posner, Bruce A.
AU - Gamo, Francisco Javier
AU - Baum, Jake
AU - Winzeler, Elizabeth A.
AU - Laleu, Benoît
AU - Ready, Joseph M.
AU - Phillips, Margaret A.
N1 - Publisher Copyright:
© 2023 American Chemical Society. All rights reserved.
PY - 2023/3/10
Y1 - 2023/3/10
N2 - Current malaria treatments are threatened by drug resistance, and new drugs are urgently needed. In a phenotypic screen for new antimalarials, we identified (S)-SW228703 ((S)-SW703), a tyrosine amide with asexual blood and liver stage activity and a fast-killing profile. Resistance to (S)-SW703 is associated with mutations in the Plasmodium falciparum cyclic amine resistance locus (PfCARL) and P. falciparum acetyl CoA transporter (PfACT), similarly to several other compounds that share features such as fast activity and liver-stage activity. Compounds with these resistance mechanisms are thought to act in the ER, though their targets are unknown. The tyramine of (S)-SW703 is shared with some reported PfCARL-associated compounds; however, we observed that strict S-stereochemistry was required for the activity of (S)-SW703, suggesting differences in the mechanism of action or binding mode. (S)-SW703 provides a new chemical series with broad activity for multiple life-cycle stages and a fast-killing mechanism of action, available for lead optimization to generate new treatments for malaria.
AB - Current malaria treatments are threatened by drug resistance, and new drugs are urgently needed. In a phenotypic screen for new antimalarials, we identified (S)-SW228703 ((S)-SW703), a tyrosine amide with asexual blood and liver stage activity and a fast-killing profile. Resistance to (S)-SW703 is associated with mutations in the Plasmodium falciparum cyclic amine resistance locus (PfCARL) and P. falciparum acetyl CoA transporter (PfACT), similarly to several other compounds that share features such as fast activity and liver-stage activity. Compounds with these resistance mechanisms are thought to act in the ER, though their targets are unknown. The tyramine of (S)-SW703 is shared with some reported PfCARL-associated compounds; however, we observed that strict S-stereochemistry was required for the activity of (S)-SW703, suggesting differences in the mechanism of action or binding mode. (S)-SW703 provides a new chemical series with broad activity for multiple life-cycle stages and a fast-killing mechanism of action, available for lead optimization to generate new treatments for malaria.
KW - PfACT
KW - PfCARL
KW - Plasmodium
KW - malaria
KW - resistance
KW - tyrosine amide
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U2 - 10.1021/acsinfecdis.2c00527
DO - 10.1021/acsinfecdis.2c00527
M3 - Article
C2 - 36763526
AN - SCOPUS:85148244538
SN - 2373-8227
VL - 9
SP - 527
EP - 539
JO - ACS infectious diseases
JF - ACS infectious diseases
IS - 3
ER -