Toxoplasma (T.) gondii, the causative agent of toxoplasmosis, is a ubiquitous opportunistic pathogen that infects both immune-competent and immune-compromised individuals worldwide, and is the leading cause of severe congenital neurological and ocular disease in humans. Toxoplasmosis is also a major opportunistic infection that causes illness, disability and death in HIV/AIDS patients. T. gondii remains a serious medical problem in this post-HAART age which justifies the commercial development of new medicines for large segments of the U.S. and world population. Infection in immune- compromised persons who are at risk for toxoplasmosis include those infected with the parasite who also have cancer, undergo organ transplantation, autoimmune disease or those who receive immunosuppressive medicine for treatment of these and other diseases. T. gondii is the leading cause of uveitis (ocular disease) in the world, causing visual impairment and blindness. Congenital toxoplasmosis is a devastating infection that occurs when a pregnant woman acquires T. gondii infection for the first time and transmits the infection to the fetus. Incidence in the U.S. is 1 per 5000 live births. Congenital toxoplasmosis can cause severe vision loss, brain damage, and even death. Primary, acute and chronic infection occurs in immune-competent people as T. gondii infection is most commonly acquired through the ingestion of contaminated food or water. Acute acquired infection is often undiagnosed or misdiagnosed because infected persons either experience lymphadenopathy or flu-like symptoms. Chronic infection occurs in approximately 1/3 to 1/2 of the world population (i.e., 2-3 billion persons).T. gondii is designated as a Category B biodefense pathogen by the NIAID due to its environmental persistence and its potential for rapid dissemination through contaminated food and water supplies. No vaccine is available, and existing small-molecule drugs for toxoplasmosis are inadequate or poorly tolerated for many patients. Therefore, an urgent need exists for the discovery of safer and more effective medicines for toxoplasmosis therapy. In response to this need, Snowdon is developing small-molecule inhibitors of an essential biological pathway exclusive to T. gondii and other Apicomplexan parasites that controls their invasive machinery necessary for survival. Specifically, these inhibitors are designed to disrupt a key protein-protein interaction between the unusual Myosin A (MyoA) and the Myosin A_Tail Interacting Protein (MTIP). Guided by computational approaches, we have already discovered a novel early-stage Drug Lead, SN_T18, that exhibits sub-micromolar inhibitory activity (IC50 <600 nM) against T. gondii in parasitic assays. SN_T18 is a simple organic molecule that is easy to synthesize, possesses good chemical stability, is non-toxic and exhibits good intestinal permeability when administered orally to mice. Starting with SN_T18, we now propose to generate and explore a focused series of SN_T18 analogs to identify the most promising compound(s) as potential drug candidates. The primary objective of this proposed study is to discover safe and effective treatments for T. gondii infection. In this project, Snowdon will employ an integrated approach that combines rational (computer-aided) design, chemical synthesis, and both in vitro and in vivo biological evaluation to attack this novel drug target. To our best knowledge, these inhibitors will be the first of their kind that target the vulnerable invasive machinery of these parasites.
Brief description This SBIR Phase I study aims to implement a novel strategy for the development of molecules targeting a key protein-protein interaction between the unusual Myosin A (MyoA) and the Myosin A Tail Interacting Protein (MTIP) in Toxoplasma (T.) gondii, as treatments for toxoplasmosis which affects HIV/AIDS patients.
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| Kortagere, Sandhya; Mui, Ernest; McLeod, Rima et al. (2011) Rapid discovery of inhibitors of Toxoplasma gondii using hybrid structure-based computational approach. J Comput Aided Mol Des 25:403-11 |
