The major goal of our research is to develop and test specific inhibitors of Trypanosoma cruzi proteinase that we hypothesize is critical to the pathogenesis of Chagas' disease. T. cruzi elaborates a cysteine proteinase which we hypothesize is required for the metabolism of the parasite within cardiac cells, and transformation between stages of the parasite life cycle. We have tested synthetic proteinase inhibitors which are effective against the enzyme, in cell culture to see the effect on parasite replication in mammalian cells. P34081 (Mu-Phe-homophe-FMK) used as our standard showed inhibition of the parasite replication. However, when the drug pressure was relived after ten days of treatment the parasites resume replication. In contrast, P35027 not only arrested parasite growth but also had trypanocidal effect clearing the cell culture of infection after 14 days of treatment at 20 5M concentration. We have now tested P35027 compound in a preliminary animal trial. No adverse effects were observed in mice treated with 2 mg/day for as long as 45 days with the pseudopeptide inhibitor. A preliminary trial showed that two 1-mg injections daily of P35027 reduced the parasitemia levels in T. cruzi-infected mice, and extends the survival of mice infected with 500 times the lethal dose (Fig. B). Survival of the mice challenged with a lower lethal dose of infection was greatly extended with doses slightly higher (3 mg/day/mice) during a 12 day period. Sometreated animals survived more than five months after infection without detectable parasitemia (Fig. C). However, A more extensive animal trial, to optimize drug dosage and treatment schedule to increase the efficacy of the inhibitors are necessary before cure can be achieved.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Biotechnology Resource Grants (P41)
Project #
5P41RR001081-21
Application #
6280208
Study Section
Project Start
1998-07-01
Project End
1999-06-30
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
21
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Type
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Kozak, John J; Gray, Harry B; Garza-López, Roberto A (2018) Relaxation of structural constraints during Amicyanin unfolding. J Inorg Biochem 179:135-145
Alamo, Lorenzo; Pinto, Antonio; Sulbarán, Guidenn et al. (2018) Lessons from a tarantula: new insights into myosin interacting-heads motif evolution and its implications on disease. Biophys Rev 10:1465-1477
Viswanath, Shruthi; Chemmama, Ilan E; Cimermancic, Peter et al. (2017) Assessing Exhaustiveness of Stochastic Sampling for Integrative Modeling of Macromolecular Structures. Biophys J 113:2344-2353
Chu, Shidong; Zhou, Guangyan; Gochin, Miriam (2017) Evaluation of ligand-based NMR screening methods to characterize small molecule binding to HIV-1 glycoprotein-41. Org Biomol Chem 15:5210-5219
Portioli, Corinne; Bovi, Michele; Benati, Donatella et al. (2017) Novel functionalization strategies of polymeric nanoparticles as carriers for brain medications. J Biomed Mater Res A 105:847-858
Alamo, Lorenzo; Koubassova, Natalia; Pinto, Antonio et al. (2017) Lessons from a tarantula: new insights into muscle thick filament and myosin interacting-heads motif structure and function. Biophys Rev 9:461-480
Nguyen, Hai Dang; Yadav, Tribhuwan; Giri, Sumanprava et al. (2017) Functions of Replication Protein A as a Sensor of R Loops and a Regulator of RNaseH1. Mol Cell 65:832-847.e4
Sofiyev, Vladimir; Kaur, Hardeep; Snyder, Beth A et al. (2017) Enhanced potency of bivalent small molecule gp41 inhibitors. Bioorg Med Chem 25:408-420
Nekouzadeh, Ali; Rudy, Yoram (2016) Conformational changes of an ion-channel during gating and emerging electrophysiologic properties: Application of a computational approach to cardiac Kv7.1. Prog Biophys Mol Biol 120:18-27
Towse, Clare-Louise; Vymetal, Jiri; Vondrasek, Jiri et al. (2016) Insights into Unfolded Proteins from the Intrinsic ?/? Propensities of the AAXAA Host-Guest Series. Biophys J 110:348-361

Showing the most recent 10 out of 508 publications