TY - JOUR
T1 - Repositioned drugs for chagas disease unveiled via structure-based drug repositioning
AU - Adasme, Melissa F.
AU - Bolz, Sarah Naomi
AU - Adelmann, Lauren
AU - Salentin, Sebastian
AU - Haupt, V. Joachim
AU - Moreno-Rodríguez, Adriana
AU - Nogueda-Torres, Benjamín
AU - Castillo-Campos, Verónica
AU - Yepez-Mulia, Lilián
AU - De Fuentes-Vicente, José A.
AU - Rivera, Gildardo
AU - Schroeder, Michael
N1 - Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2020/11/2
Y1 - 2020/11/2
N2 - Chagas disease, caused by the parasite Trypanosoma cruzi, affects millions of people in South America. The current treatments are limited, have severe side effects, and are only partially effective. Drug repositioning, defined as finding new indications for already approved drugs, has the potential to provide new therapeutic options for Chagas. In this work, we conducted a structure-based drug repositioning approach with over 130,000 3D protein structures to identify drugs that bind therapeutic Chagas targets and thus represent potential new Chagas treatments. The screening yielded over 500 molecules as hits, out of which 38 drugs were prioritized following a rigorous filtering process. About half of the latter were already known to have trypanocidal activity, while the others are novel to Chagas disease. Three of the new drug candidates—ciprofloxacin, naproxen, and folic acid—showed a growth inhibitory activity in the micromolar range when tested ex vivo on T. cruzi trypomastigotes, validating the prediction. We show that our drug repositioning approach is able to pinpoint relevant drug candidates at a fraction of the time and cost of a conventional screening. Furthermore, our results demonstrate the power and potential of structure-based drug repositioning in the context of neglected tropical diseases where the pharmaceutical industry has little financial interest in the development of new drugs.
AB - Chagas disease, caused by the parasite Trypanosoma cruzi, affects millions of people in South America. The current treatments are limited, have severe side effects, and are only partially effective. Drug repositioning, defined as finding new indications for already approved drugs, has the potential to provide new therapeutic options for Chagas. In this work, we conducted a structure-based drug repositioning approach with over 130,000 3D protein structures to identify drugs that bind therapeutic Chagas targets and thus represent potential new Chagas treatments. The screening yielded over 500 molecules as hits, out of which 38 drugs were prioritized following a rigorous filtering process. About half of the latter were already known to have trypanocidal activity, while the others are novel to Chagas disease. Three of the new drug candidates—ciprofloxacin, naproxen, and folic acid—showed a growth inhibitory activity in the micromolar range when tested ex vivo on T. cruzi trypomastigotes, validating the prediction. We show that our drug repositioning approach is able to pinpoint relevant drug candidates at a fraction of the time and cost of a conventional screening. Furthermore, our results demonstrate the power and potential of structure-based drug repositioning in the context of neglected tropical diseases where the pharmaceutical industry has little financial interest in the development of new drugs.
KW - Chagas
KW - Drug repositioning
KW - Non-covalent interactions
KW - Structural screening
KW - Trypanosoma cruzi
UR - http://www.scopus.com/inward/record.url?scp=85096318680&partnerID=8YFLogxK
U2 - 10.3390/ijms21228809
DO - 10.3390/ijms21228809
M3 - Artículo
C2 - 33233837
AN - SCOPUS:85096318680
SN - 1661-6596
VL - 21
SP - 1
EP - 22
JO - International Journal of Molecular Sciences
JF - International Journal of Molecular Sciences
IS - 22
M1 - 8809
ER -