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Indel‐based targeting of essential proteins in human pathogens that have close host orthologue(s): Discovery of selective inhibitors for Leishmania donovani elongation factor‐1α
Author(s) -
Nandan Devki,
Lopez Martin,
Ban Fuqiang,
Huang Meilan,
Li Yvonne,
Reiner Neil E.,
Cherkasov Artem
Publication year - 2007
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/prot.21278
Subject(s) - indel , biology , leishmania , human pathogen , leishmania donovani , computational biology , pathogen , drug discovery , small molecule , genetics , biochemistry , gene , leishmaniasis , visceral leishmaniasis , parasite hosting , genotype , single nucleotide polymorphism , computer science , world wide web
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‐1α (EF‐1α) from the protozoan pathogen Leishmania donovani . Leishmania EF‐1α is 82% identical to the corresponding human orthologue, but possesses a 12 aminoacid sequence deletion compared with human EF‐1α. We used this indel‐differentiated region to design small molecules that selectively bind to leishmania EF‐1α 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. Proteins 2007. © 2007 Wiley‐Liss, Inc.