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Table 2 A list of efficient anti-malarial aaRS inhibitors

From: Recent advances in the biology and drug targeting of malaria parasite aminoacyl-tRNA synthetases

Inhibitor

Target plasmoDB geneID

Comment

Mupirocin

IleRS

PF3D7_1225100

This is a clinical inhibitor of bacterial infection by S. aeurus. Likely targets active site of apicoplast IleRS with IC50 ~ 90 nM [21]

4-Thiaisoleucine

IleRS

PF3D7_1332900

Structural analogue of isoleucine targets the cytoplasmic IleRS [21]

TCMDC-131575

IleRS

PF3D7_1332900

Molecule identified in GlaxoSmithKline’s library screening. IleRS is the hypothesized target [45]

Cladosporin

LysRS

PF3D7_1350100

A selective malaria inhibitor with IC50 value near 50 nM. Kills both liver and blood stage parasites. Drug bound crystal structure is available [40, 41]

Lysyl-adenylate analogues

LysRS

PF3D7_1416800

Nearly 50 analogues with μM inihibition reported [46]

Halofuginone

ProRS

PF3D7_1213800

Inhibit both liver and blood stages. Bind to parasite enzyme with Kd value of 9 nM. Halofuginone bound crystal structure is available [43, 52, 55]

Borrelidin and analogues

ThrRS

PF3D7_1126000

Kills P. falciparum at IC50 near 1 nM. ThrRS inhibition confirmed in enzyme assays [40]. Analogs with reduced cytotoxicity to human were reported [42, 47–49]

A5, A3

AlaRS

PF3D7_1367700

Several P. falciparum inhibitors identified using in silico screening and docking against active site. A5 was top inhibitor with IC50 value near 4 μM [18]

TCMDC-141232

TyrRS

PF3D7_1117500

Molecule identified in GlaxoSmithKline’s library screening. Apicoplast copy of TyrRS is the hypothesized target [45]

REP3123

REP8839

C1–C8

MetRS

PF3D7_1034900

Known bacterial MetRS inhibitors REP3123 and REP8839 inhibit P. falciparum and block translation with IC50 values near 150 nM. C1–C8 identified from in silico screening and inhibit parasite growth with IC50 values below 500 nM [24]

TCMDC-140014

TCMDC-139627

TCMDC-139450

MetRS

PF3D7_1034900

Molecules identified in GlaxoSmithKline’s library screening. MetRS is the hypothesized target [45]

Sulfomyl adenosine analogues

SerRS

PF3D7_071770

GluRS

PF3D7_1349200

GlnRS

PF3D7_1331700

AsnRS

PF3D7_0211800

TyrRS

PF3D7_0807900

Mechanism based inhibitors that mimic the intermediate aminoacyl-AMP were tested and shown to kill malaria parasite in nM values [42]

AN2729

LeuRS

PF3D7_0828200

Member of benzoxaborols family which show anti-malarial activity [42]

TCMDC-140398

TCMDC-140498

TCMDC-140522

TCMDC-140563

TCMDC-140564

TCMDC-140734

TCMDC-141485

PheRS

PF3D7_1104000

Molecule identified in GlaxoSmithKline’s library screening. Cytoplasmic copy of PheRS is the hypothesized target [45]