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Bioorg Med Chem Lett ; 25(10): 2065-7, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25900220

RESUMO

Cryptosporidiosis, a gastrointestinal disease caused by protozoans of the genus Cryptosporidium, is a common cause of diarrheal diseases and often fatal in immunocompromised individuals. Bifunctional thymidylate synthase-dihydrofolate reductase (TS-DHFR) from Cryptosporidium hominis (C. hominis) has been a molecular target for inhibitor design. C. hominis TS-DHFR inhibitors with nM potency at a biochemical level have been developed however drug delivery to achieve comparable antiparasitic activity in Cryptosporidium infected cell culture has been a major hurdle for designing effective therapies. Previous mechanistic and structural studies have identified compound 906 as a nM C. hominis TS-DHFR inhibitor in vitro, having µM antiparasitic activity in cell culture. In this work, proof of concept studies are presented using a nanotherapy approach to improve drug delivery and the antiparasitic activity of 906 in cell culture. We utilized PLGA nanoparticles that were loaded with 906 (NP-906) and conjugated with antibodies to the Cryptosporidium specific protein, CP2, on the nanoparticle surface in order to specifically target the parasite. Our results indicate that CP2 labeled NP-906 (CP2-NP-906) reduces the level of parasites by 200-fold in cell culture, while NP-906 resulted in 4.4-fold decrease. Moreover, the anticryptosporidial potency of 906 improved 15 to 78-fold confirming the utility of the antibody conjugated nanoparticles as an effective drug delivery strategy.


Assuntos
Antiprotozoários/farmacologia , Cryptosporidium/efeitos dos fármacos , Cryptosporidium/enzimologia , Complexos Multienzimáticos/antagonistas & inibidores , Nanopartículas/química , Timidilato Sintase/antagonistas & inibidores , Antiprotozoários/síntese química , Antiprotozoários/química , Sítios de Ligação , Células Cultivadas , Sinergismo Farmacológico , Modelos Moleculares , Tetra-Hidrofolato Desidrogenase
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