Rapid discovery of inhibitors of Emphasis Type="I

Authors: Sandhya Kortagere Ernest Mui Rima McLeod William J Welsh

Publish Date: 2011/02/26

Volume: 25, Issue: 5, Pages: 403-411

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Abstract

Toxoplasma T gondii the causative agent of toxoplasmosis is a ubiquitous opportunistic pathogen that infects individuals worldwide and is a leading cause of severe congenital neurologic and ocular disease in humans No vaccine to protect humans is available and hypersensitivity and toxicity limit the use of the few available medicines Therefore safer and more effective medicines to treat toxoplasmosis are urgently needed Using the Hybrid Structure Based HSB method we have previously identified small molecule inhibitors of P falciparum that seem to target a novel protein–protein interaction between the Myosin tail interacting protein and myosin light chain This pathway has been hypothesized to be involved in invasion of host erythrocytes by the parasite and is broadly conserved among the apicomplexans Guided by similar computational drug design approaches we investigated this series of small molecules as potential inhibitors of T gondii Compound C321 identified as the most active inhibitor in this series exhibited an IC50 value ~500 nM against T gondii Among the 16 structural analogs of C321 tested thus far nine additional compounds were identified with IC50 values 100 μM In vitro assays have revealed that C321 markedly limits intracellular growth of T gondii tachyzoites but has no effect on host cell human foreskin fibroblasts HFF at concentrations more than a log greater than the concentration that inhibits the parasitesThis work was funded in part by grant NIH R21GM081394 to WJW from the National Institute of General Medical Sciences Funding for this research was also provided to WJW by US Army Small Business Innovation Research SBIR program contract W81XWH04C0024 This research project was also made possible by a grant that was awarded by the Center for Military Biomaterial Research CeMBR of Rutgers University and administered by the US Army Medical Research and Materiel Command USAMRMC and the Telemedicine Advanced Technology Research Center TATRC Fort Detrick Maryland 21702 under Contract Number W81XWH0420031 This work was also funded by the NIHNIAID Grant R43AI078763 to RM and WJW The views opinions and findings contained in this research are those of the participating laboratories and do not necessarily reflect the views of the Department of Defense and should not be construed as an official DoD/Army policy unless so designated by other documentation No official endorsement should be made We thank Dr Sean Ekins for thoughtful discussions

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