Two approaches to discovering and developing new drugs for Chagas disease.
This review will focus on two general approaches carried out at the Sandler Center, University of California, San Francisco, to address the challenge of developing new drugs for the treatment of Chagas disease. The first approach is target-based drug discovery, and two specific targets, cytochrome P450 CYP51 and cruzain (aka cruzipain), are discussed. A 'proof of concept' molecule, the vinyl sulfone inhibitor K777, is now a clinical candidate. The preclinical assessment compliance for filing as an Investigational New Drug with the United States Food and Drug Administration (FDA) is presented, and an outline of potential clinical trials is given. The second approach to identifying new drug leads is parasite phenotypic screens in culture. The development of an assay allowing high throughput screening of Trypanosoma cruzi amastigotes in skeletal muscle cells is presented. This screen has the advantage of not requiring specific strains of parasites, so it could be used with field isolates, drug resistant strains or laboratory strains. It is optimized for robotic liquid handling and has been validated through a screen of a library of FDA-approved drugs identifying 65 hits.
McKerrow
J H
JH
Sandler Center at Mission Bay, University of California, San Francisco, CA 94158-2330, USA. jmck@cgl.ucsf.edu
Doyle
P S
PS
Engel
J C
JC
Podust
L M
LM
Robertson
S A
SA
Ferreira
R
R
Saxton
T
T
Arkin
M
M
Kerr
I D
ID
Brinen
L S
LS
Craik
C S
CS
D000818:Animals; D014355:Chagas Disease / Q000188:drug therapy*; D003546:Cysteine Endopeptidases; D015853:Cysteine Proteinase Inhibitors / Q000627:therapeutic use*; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; D004151:Dipeptides / Q000627:therapeutic use*; D015195:Drug Design; D006801:Humans; D010649:Phenylalanine / Q000031:analogs & derivatives; D010879:Piperazines; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors; D014105:Tosyl Compounds; D014344:Trypanocidal Agents / Q000627:therapeutic use*; D014481:United States; D014486:United States Food and Drug Administration; D014753:Vinyl Compounds / Q000627:therapeutic use*
C509352:CYP51 protein, Trypanosoma cruzi; D015853:Cysteine Proteinase Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D004151:Dipeptides; D010879:Piperazines; D015800:Protozoan Proteins; D014105:Tosyl Compounds; D014344:Trypanocidal Agents; D014753:Vinyl Compounds; C487484:N-pip-phenylalanine-homophenylalanine-vinyl sulfone phenyl; D010649:Phenylalanine; D003577:Cytochrome P-450 Enzyme System; D003546:Cysteine Endopeptidases; C074032:cruzain, Trypanosoma cruzi