#METABOLOMICS WORKBENCH eallman_20190808_174524 DATATRACK_ID:1791 STUDY_ID:ST001239 ANALYSIS_ID:AN002058 PROJECT_ID:PR000829
VERSION             	1
CREATED_ON             	August 13, 2019, 4:44 pm
#PROJECT
PR:PROJECT_TITLE                 	Antimalarial pantothenamide metabolites target acetyl-CoA biosynthesis in
PR:PROJECT_TITLE                 	Plasmodium falciparum
PR:PROJECT_SUMMARY               	Malaria eradication is critically dependent on new therapeutics that target
PR:PROJECT_SUMMARY               	resistant Plasmodium parasites and block transmission of the disease. Here, we
PR:PROJECT_SUMMARY               	report the discovery of potent pantothenamide bioisosteres that are active
PR:PROJECT_SUMMARY               	against blood-stage Plasmodium falciparum parasites and that block transmission
PR:PROJECT_SUMMARY               	of sexual stages to the mosquito vector. These compounds were resistant to
PR:PROJECT_SUMMARY               	degradation by serum pantetheinases, showed favorable pharmacokinetic properties
PR:PROJECT_SUMMARY               	and cleared parasites in a humanized mouse infection model of P. falciparum.
PR:PROJECT_SUMMARY               	Metabolomics revealed that CoA biosynthetic enzymes converted pantothenamides
PR:PROJECT_SUMMARY               	into CoA-analogs that interfered with parasite acetyl-CoA anabolism. In vitro
PR:PROJECT_SUMMARY               	generated resistant parasites showed mutations in acetyl-CoA synthetase and
PR:PROJECT_SUMMARY               	acyl-CoA synthetase 11. Introduction and reversion of these mutations in P.
PR:PROJECT_SUMMARY               	falciparum by CRISPR/Cas9 gene editing confirmed the key roles of these enzymes
PR:PROJECT_SUMMARY               	in the sensitivity of the malaria parasite to pantothenamides. These
PR:PROJECT_SUMMARY               	pantothenamide compounds with a unique mode of action may have potential as
PR:PROJECT_SUMMARY               	drugs against malaria parasites.
PR:INSTITUTE                     	Penn State
PR:LAST_NAME                     	Llinas
PR:FIRST_NAME                    	Manuel
PR:ADDRESS                       	W126 Millennium Science Complex, University Park, PENNSYLVANIA, 16802, USA
PR:EMAIL                         	mul27@psu.edu
PR:PHONE                         	(814) 867-3527
#STUDY
ST:STUDY_TITLE                   	NMR assignment of synthetic pantothenamides (part-II)
ST:STUDY_SUMMARY                 	1H and 13C NMR of synthesized pantothenamides used for in vitro metabolomics
ST:STUDY_SUMMARY                 	studies.
ST:INSTITUTE                     	Penn State
ST:LAST_NAME                     	Llinas
ST:FIRST_NAME                    	Manuel
ST:ADDRESS                       	W126 Millennium Science Complex, University Park, PENNSYLVANIA, 16802, USA
ST:EMAIL                         	mul27@psu.edu
ST:PHONE                         	(814) 867-3527
#SUBJECT
SU:SUBJECT_TYPE                  	Other
SU:SUBJECT_SPECIES               	Synthetic
#SUBJECT_SAMPLE_FACTORS:         	SUBJECT(optional)[tab]SAMPLE[tab]FACTORS(NAME:VALUE pairs separated by |)[tab]Additional sample data
SUBJECT_SAMPLE_FACTORS           	-	006_1H	Spectra:1H NMR	Type=CXP18.6-006
SUBJECT_SAMPLE_FACTORS           	-	006_13C	Spectra:13C NMR	Type=CXP18.6-006
SUBJECT_SAMPLE_FACTORS           	-	017_1H	Spectra:1H NMR	Type=CXP18.6-017
SUBJECT_SAMPLE_FACTORS           	-	017_13C	Spectra:13C NMR	Type=CXP18.6-017
SUBJECT_SAMPLE_FACTORS           	-	026_1H	Spectra:1H NMR	Type=CXP18.6-026
SUBJECT_SAMPLE_FACTORS           	-	026_13C	Spectra:13C NMR	Type=CXP18.6-026
SUBJECT_SAMPLE_FACTORS           	-	052_1H	Spectra:1H NMR	Type=CXP18.6-052
SUBJECT_SAMPLE_FACTORS           	-	052_13C	Spectra:13C NMR	Type=CXP18.6-052
SUBJECT_SAMPLE_FACTORS           	-	052_HSQC	Spectra:HSQC NMR	Type=CXP18.6-052
SUBJECT_SAMPLE_FACTORS           	-	258_1H	Spectra:1H NMR	Type=MMV689258
SUBJECT_SAMPLE_FACTORS           	-	258_13C	Spectra:13C NMR	Type=MMV689258
SUBJECT_SAMPLE_FACTORS           	-	968_1H	Spectra:1H NMR	Type=MMV884968
SUBJECT_SAMPLE_FACTORS           	-	968_13C	Spectra:13C NMR	Type=MMV884968
#COLLECTION
CO:COLLECTION_SUMMARY            	Synthesized compounds were freeze dried and resuspended in MeOD between 10-20mM.
CO:COLLECTION_SUMMARY            	Samples were then placed into NMR sample tubes for analysis.
CO:SAMPLE_TYPE                   	Synthetic chemistry
#TREATMENT
TR:TREATMENT_SUMMARY             	No treatment, these synthetic compounds tested for structure accuracy and
TR:TREATMENT_SUMMARY             	purity.
#SAMPLEPREP
SP:SAMPLEPREP_SUMMARY            	Several of the original synthesized compounds were in DMSO. This was removed, to
SP:SAMPLEPREP_SUMMARY            	the best of our ability, using a freeze dryer before dissolving in MeOD.
#ANALYSIS
AN:ANALYSIS_TYPE                 	NMR
#NMR
NM:INSTRUMENT_NAME               	Bruker AVIII-HD-500
NM:INSTRUMENT_TYPE               	FT-NMR
NM:NMR_EXPERIMENT_TYPE           	Other
NM:SPECTROMETER_FREQUENCY        	500 MHz
#END