Indel-based targeting of essential proteins in human pathogens that have close host orthologue(s): discovery of selective inhibitors for Leishmania donovani elongation factor-1alpha.
We propose a novel strategy for selective targeting of essential pathogen proteins that contain sizable indels (insertions/deletions) in their sequences compared with their host orthologues. This approach has been tested on elongation factor-1alpha (EF-1alpha) from the protozoan pathogen Leishmania donovani. Leishmania EF-1alpha is 82% identical to the corresponding human orthologue, but possesses a 12 aminoacid sequence deletion compared with human EF-1alpha. We used this indel-differentiated region to design small molecules that selectively bind to leishmania EF-1alpha and not to the human protein. Three unrelated molecules were identified with the capacity to inhibit protein synthesis in leishmania by up to 75% while exhibiting no effect on human protein translation. These candidates may serve as prototypes for future development of antiprotozoan therapeutics. More generally, these findings provide a basis for a novel drug design platform. This platform targets essential pathogen proteins that are highly conserved across species, and consequently would not typically be considered to be conventional drug targets. We anticipate that such indel-directed targeting of essential proteins in microbial pathogens may help address the growing problem of antibiotic resistance.
Nandan
Devki
D
Division of Infectious Diseases, Department of Medicine, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
Lopez
Martin
M
Ban
Fuqiang
F
Huang
Meilan
M
Li
Yvonne
Y
Reiner
Neil E
NE
Cherkasov
Artem
A
D000595:Amino Acid Sequence; D000818:Animals; D001559:Benzhydryl Compounds / Q000494:pharmacology; D001665:Binding Sites; D002396:Catechols / Q000494:pharmacology; D002474:Cell-Free System; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D019295:Computational Biology; D003198:Computer Simulation; D017353:Gene Deletion; D006801:Humans; D006860:Hydrogen Bonding; D007893:Leishmania donovani / Q000187:drug effects / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009281:Naphthalenes / Q000494:pharmacology; D020648:Peptide Elongation Factor 1 / Q000037:antagonists & inhibitors*; D010648:Phenylacetates / Q000494:pharmacology; D015800:Protozoan Proteins / Q000235:genetics*; D016415:Sequence Alignment; D013449:Sulfonamides / Q000494:pharmacology
D001559:Benzhydryl Compounds; D002396:Catechols; D002867:Chromones; C519301:NSC 122281; C519302:NSC 36398; C519303:NSC 4347; D009281:Naphthalenes; D020648:Peptide Elongation Factor 1; D010648:Phenylacetates; D015800:Protozoan Proteins; D013449:Sulfonamides