Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: UMLS:C0024530 (
malaria
)
44,886
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Malaria
and cryptosporidiosis, caused by apicomplexan parasites, remain major drivers of global child mortality. New drugs for the treatment of
malaria
and cryptosporidiosis, in particular, are of high priority; however, there are few chemically validated targets. The natural product cladosporin is active against blood- and liver-stage
Plasmodium falciparum
and
Cryptosporidium parvum
in cell-culture studies. Target deconvolution in
P. falciparum
has shown that cladosporin inhibits lysyl-tRNA synthetase (
Pf
KRS1). Here, we report the identification of a series of selective inhibitors of apicomplexan KRSs. Following a biochemical screen, a small-molecule hit was identified and then optimized by using a structure-based approach, supported by structures of both
Pf
KRS1 and
C. parvum
KRS
(
Cp
KRS
). In vivo proof of concept was established in an SCID mouse model of
malaria
, after oral administration (ED
90
= 1.5 mg/kg, once a day for 4 d). Furthermore, we successfully identified an opportunity for pathogen hopping based on the structural homology between
Pf
KRS1 and
Cp
KRS
. This series of compounds inhibit
Cp
KRS
and
C. parvum
and
Cryptosporidium hominis
in culture, and our lead compound shows oral efficacy in two cryptosporidiosis mouse models. X-ray crystallography and molecular dynamics simulations have provided a model to rationalize the selectivity of our compounds for
Pf
KRS1 and
Cp
KRS
vs. (human)
Hs
KRS
. Our work validates apicomplexan KRSs as promising targets for the development of drugs for
malaria
and cryptosporidiosis.
...
PMID:Lysyl-tRNA synthetase as a drug target in malaria and cryptosporidiosis. 3089 87
Cladosporin (CLD) is a fungal metabolite that kills the
malaria
parasite via inhibiting its cytoplasmic lysyl-tRNA synthetase (
KRS
) and abrogating protein translation. Here we provide structural and drug selectivity analyses on CLD interacting residues in apo and holo KRSs from Plasmodium falciparum, Homo sapiens, Cryptosporidium parvum, and Mycobacterium ulcerans. We show that both gross and subtle alterations in protein backbone and sidechains drive the active site structural plasticity that allows integration of CLD in KRSs. The ligand-induced fit of CLD in PfKRS is marked by closure and stabilization of three disordered loops and one alpha helix. However, these structural rearragements are not evident in
KRS
-CLD complexes from H. sapiens, C. parvum, or M. ulcerans. Strikingly, CLD fits into the MuKRS active site due to a remarkable rotameric alteration in its clash-prone methionine residue that provides accommodation for the methyl moiety in CLD. Although the high concentrations of drugs used for Hs, Cp, and MuKRS-CLD complexes in co-crystallization studies enable elucidation of a structural framework for understanding drug binding in KRSs, we propose that these data should be concurrently assessed via biochemical studies of potency and drug selectivity given the poor cell-based activity of CLD against human and bacterial cells. Our comprehensive analyses of
KRS
-CLD interactions, therefore, highlight vital issues in structure-based drug discovery studies.
...
PMID:Side chain rotameric changes and backbone dynamics enable specific cladosporin binding in Plasmodium falciparum lysyl-tRNA synthetase. 3101 32
