Inhibitors of Mycobacterial Protein Tyrosine Phosphatase B (mPTPB) for therapy of tuberculosis Aarden Pharmaceuticals Project Summary/Abstract The need exists for a new, breakthrough therapeutic for tuberculosis (TB). Current treatment regimens with toxic chemotherapeutic drugs are too long, causing poor compliance which results in reduced efficacy and the emergence of drug-resistant strains due to incomplete clearance of the infection, resulting in over 1.7 million deaths annually. The WHO has now made the elimination of TB as one of its global development goals of the millennium. The key unmet needs/wants for TB therapy are to shorten the current 6-9 month treatment duration and maintain effectiveness against multidrug resistant TB. Mycobacterial Protein Tyrosine Phosphatase B (mPTPB) is a member of the protein tyrosine phosphatase family of enzymes. TB bacteria encourage their engulfment by host cells of the innate immune system and then 'hide' from and interfere with host immune responses inside these cells. mPTPB is actively secreted into the cytoplasm of infected macrophages, where it undermines host antibacterial defense mechanisms by blocking the production of inflammatory cytokines and preventing the execution of the infected macrophage's 'Plan B', which is to undergo apoptosis to cause death of the infected cell (and its bacterial passengers) for the good of the organism as a whole. In collaboration with our academic cofounder Zhong-Yin Zhang, Aarden has discovered and characterized several generations of mPTPB inhibitors of increasing potency and selectivity. The most advanced compounds, the L01-Z series, exhibit low nanomolar potency against mPTPB in biochemical and cellular activity assays and display a high degree of selectivity for mPTPB. The lead compound, L01-Z08, is active in a guinea pig model of TB infection. The primary objective of the current proposal is to complete the characterization and Lead Optimization of LO1-Z08, for the treatment of TB, leading to the nomination of L01-Z08 as a clinical development candidate for TB. The secondary objective is the discovery and initial characterization of one or more families of backup compounds with diverse chemical structures. The Specific Aims of the project are: (i) To determine the precise mechanisms of action of L01-Z08 and related compounds in cellular systems by multiple biochemical and recombinant approaches and characterize the activity of mPTPB inhibitors in TB-infected macrophages in vitro (ii) To complete pharmaceutics analyses of L01-Z08 and related compounds, including in vitro ADME, CEREP screen, genetox/micronucleus assays (iii) To synthesize 50-100g of L01-Z08, complete a standard screen to identify a clinical formulation, determine oral bioavailability and perform preliminary toxicology in the rat (iv) To identify potential backup compounds from pre-existing libraries of PTP inhibitors
Public Health Relevance Statement: Public Health Relevance: The need exists for a new, breakthrough therapeutic for TB - despite the disease burden and the loss of life caused by TB, no new class of drugs has been approved for the treatment of the disease since the 1970s. Current treatment regimens with toxic chemotherapy-type drugs are a too long, causing patient to stop taking the drugs too early, which leads to the emergence of drug-resistant strains of TB. Over a third of world's population is infected with TB, resulting in over 1.7 million deaths annually, and the WHO has now made the elimination of TB as one of its global development goals of the millennium.
Project Terms: abstracting; Anti-Bacterial Agents; Apoptosis; Bacteria; Biochemical; Biological Assay; Biological Availability; burden of illness; Cause of Death; Cavia; Cells; Cessation of life; Chemical Structure; chemotherapy; Clinical; Collaborations; cytokine; Cytoplasm; Defense Mechanisms; Development; Disease; Drug Formulations; Drug resistance; Effectiveness; Enzymes; Exhibits; Family; Family member; Foundations; Generations; Goals; Grant; Health; Immune response; Immune system; In Vitro; in vivo; Infection; Inflammatory; inhibitor/antagonist; Laboratories; Lead; Libraries; Life; macrophage; MAP Kinase Gene; MAPK14 gene; Mediating; member; Micronucleus Tests; Modeling; Multidrug-Resistant Tuberculosis; mycobacterial; Oral; Organism; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Pharmacy (field); Phase; Plan B; Population; pre-clinical; preclinical study; Preclinical Testing; prevent; Production; Protein Tyrosine Phosphatase; Proto-Oncogene Proteins c-akt; prototype; Rat-1; Rattus; Recombinants; Reporting; research study; resistant strain; screening; Series; Signal Transduction; System; Therapeutic; Therapeutic Index; Toxicology; treatment duration; Treatment Protocols; Tuberculosis; tuberculosis drugs; tuberculosis treatment; Yin
