Analogs of natural aminoacyl-tRNA synthetase inhibitors clear malaria in vivo
Edited
by Susan A. Martinis, University of Illinois, Urbana, IL, and accepted
by the Editorial Board November 10, 2014 (received for review April 4,
2014)
(Kuten Itedale Namro Redwan 2012 teesissään mainitsi luonnosta löytyy aminohappo-tRNA syntaasien vastavaikuttajia, mutta niitä ei voi muokkaamatta käyttää, koska ne ovat toksisia.
Ensimmäinen luettelossa oli iholla käytettävissä oleva Bactrobam. Muut olivat:
indolmysiini, purppuromysiini, granatisiini, borrelidiini, okratoksiini A, furanomysiini, cis-pentasiini, askamysiini. Nyt löytämässäni artikkelissa kerrotaan borrelidiinistä johdetuista valmisteista ja niillä on myös anti- threonyl tRNA syntetaasi- vaikutusta. Otan tästä sitaatin. Ainakin hiirillä on todettu voitavan puhdistaa kehoa eräästä malariaplasmodilajista (P.Yoelii) 100%:sti. Ehkä vuoden 2014 jälkeen on saatu jotain kliinisesti käytettävissä olevaa TARS-inihiittoria. Sellaisesta saattaisi olla antivirus vaikutusta aivan lyhyinä heikentävinä kuureina virusreplikaatioryöppyä vastaan.tai ehkä jonkin muun aminohapon kuin treoniinin AaRS- inhibiittori olisi tässä pätevin moduloija).
Significance
Malaria
remains one of the main health threats in the developing world, with
staggering social and economic costs. Resistance to artemisins, the main
pharmacological tool currently available against malaria, has been
widely reported. Borrelidin, a natural compound that inhibits
threonyl-tRNA synthetase (TARS) , has long been studied for its antibacterial
and antiparasitic properties, but undesirable toxic effects prevented
its further clinical development.
Here we present a group of borrelidin
derivatives that retain their ability to inhibit Plasmodium
threonyl-tRNA synthetase but not its human homolog TARS. Furthermore, we
demonstrate, for the first time to our knowledge, that these compounds
are capable of effectively clearing a Plasmodium infection in animals, curing malaria with a potency equivalent to reference drugs such as chloroquine.
Abstract
Malaria
remains a major global health problem. Emerging resistance to existing
antimalarial drugs drives the search for new antimalarials, and protein
translation is a promising pathway to target. Here we explore the
potential of the aminoacyl-tRNA synthetase (ARS) family as a source of
antimalarial drug targets. First, a battery of known and novel ARS
inhibitors was tested against Plasmodium falciparum cultures,
and their activities were compared. Borrelidin, a natural inhibitor of
threonyl-tRNA synthetase (ThrRS), stands out for its potent antimalarial
effect. However, it also inhibits human ThrRS, TARS and is highly toxic to
human cells. To circumvent this problem, we tested a library of
bioengineered and semisynthetic borrelidin analogs for their
antimalarial activity and toxicity. We found that some analogs
effectively lose their toxicity against human cells while retaining a
potent antiparasitic activity both in vitro and in vivo and cleared
malaria from Plasmodium yoelii-infected mice, resulting in 100%
mice survival rates. Our work identifies borrelidin analogs as potent,
selective, and unexplored scaffolds that efficiently clear malaria both
in vitro and in vivo.
Lie uusinta tältä alalta. Vaikuttaa siltä että tällä alalla on kiivas tutkimus menossa.
https://www.sciencedirect.com/science/article/abs/pii/S0223523419310931?via%3Dihub
Lie uusinta tältä alalta. Vaikuttaa siltä että tällä alalla on kiivas tutkimus menossa.
https://www.sciencedirect.com/science/article/abs/pii/S0223523419310931?via%3Dihub
Discovery of novel tRNA-amino acid dual-site inhibitors against threonyl-tRNA synthetase by fragment-based target hopping
Muistiin 6.7. 2020
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