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WORCESTER, MA, United States

Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: STTR | Phase: Phase I | Award Amount: 576.67K | Year: 2015

DESCRIPTION provided by applicant Ebola EBOV and Marburg MARV viruses belong to the family Filoviridae and can cause fatal hemorrhagic fevers characterized by widespread tissue destruction with an incubation period of days Because of the safety concerns these viruses are designated as biosafety level agents Currently there is no effective vaccine or therapeutic treatment against filoviral infection and pathogenesis in humans Although several promising vaccine candidates have been shown to be effective in eliciting host immune responses and to protect primates against viral infection the minimal time required for vaccination at least one month and the sporadic nature of outbreaks reinforce the urgent need to develop potent small molecule inhibitors against filoviral infections Thus it is imperative to identify and develop potent inhibitors against filoviral infection These inhibitors are considered to be of paramount importance for use during filoviral outbreaks or bioterrorist attacks This application defines a plan to develop potent small molecule inhibitors which block entry of EBOV and MARV into host cells Entry of EBOV and MARV is mediated by a single viral glycoprotein GP which is considered one of the major therapeutic targets GP consists of two subunits GP and GP GP is responsible for receptor binding and host tropism while GP mediates viral cell membrane fusion and viral entry We have used an HTS protocol targeting GP mediated viral entry to screen a small molecule library and we have identified compounds that inhibit entry of infectious EBOV MARV IC values M These hit compounds exhibit selectivity for EBOV MARV entry The overall objective of this Phase I application is to develop these inhibitors as potential anti filoviral therapeutics This application will focus on the folloing three specific aims Synthesize structurally diverse analogs of the anti Ebola SB hit series based on structure activity relationships SARs to improve potency and selectivity Validate the lead inhibitor candidates in the infectious assay and investigate the mechanism of action MOA of the EBOV MARV inhibitors Select EBOV MARV inhibitors with in vitro ADME properties suitable for i v and oral dosing PUBLIC HEALTH RELEVANCE This project is to discover and develop small molecule entry inhibitors for Ebola and Marburg viral infection The proposed research will help to develop potential antiviral therapeutics


Patent
Microbiotix, Inc | Date: 2012-07-13

Organic compounds showing the ability to inhibit effector toxin secretion or translocation mediated by bacterial type III secretion systems are disclosed. The disclosed type III secretion system inhibitor compounds are useful for combating infections by Gram-negative bacteria such as


Patent
Microbiotix, Inc | Date: 2012-07-13

Organic compounds showing the ability to inhibit effector toxin secretion or translocation mediated by bacterial type III secretion systems are disclosed. The disclosed type III secretion system inhibitor compounds are useful for combating infections by Gram-negative bacteria such as


Patent
Microbiotix, Inc | Date: 2014-05-03

Novel compounds are disclosed having the structure of Formula I: wherein, n is an integer from 1 to 5; X is CN, F, Cl, Br, I, NO2; W is S, SO, SO2, O, NH, or NR5; R5 is alkyl, aralkyl, alkenyl, or alkynyl; Y is O, S; Z is NR1R2 or heterocycloalkyl; R1, R2 are, independently, hydrogen, alkyl, aralkyl, alkenyl, alkynyl, or cycloalkyl and may be optionally substituted with halo, hydroxy, alkoxy, amino, alkylamino, carboxy, alkoxycarbonyl, or nitrile groups; R3 and R4 are, independently, hydrogen, alkyl, aralkyl, alkenyl, alkynyl, or cycloalkyl and may be optionally substituted with halo, hydroxy, alkoxy, amino, alkylamino, carboxy, alkoxycarbonyl, or nitrile groups, and may together form a cyclic structure; and Ar is mono-, di-, or tri-substituted phenyl or heteroaryl, a pharmaceutically acceptable salts thereof. The compounds are potent bacterial efflux pump inhibitors (EPIs). Such compounds are useful to potentiate the antimicrobial activity of antimicrobial compounds such as beta-lactam antibiotics and quinolone antibiotics against Gram-negative bacteria.


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: STTR | Phase: Phase I | Award Amount: 576.80K | Year: 2015

DESCRIPTION provided by applicant The increasing prevalence of drug resistant bacterial infections highlights the critical medical need for new agents that are not susceptible to existing resistance mechanisms Few new agents are in development for Gram negative bacteria which take up small molecules sparingly and efflux most compounds that reach the periplasm A particularly problematic group are the multi drug resistant MDR Gram negatives including Acinetobacter baumannii Pseudomonas aeruginosa and Klebsiella pneumoniae Treatment of infections by these pathogens is complicated by acquired and intrinsic multi drug resistances The overall goal of this proposal is to address this critical medical need by discovering novel classes of antibacterials that are not subject to existing resistance mechanisms and developing them into new therapeutic or adjunctive agents for the treatment of MDR Gram negative infections The strategy is to focus on an unexploited essential function lipoprotein biosynthesis which is conserved in Gram negative bacteria and without homologs mammals Following translocation across the inner membrane lipoprotein precursors are acylated by lipoprotein diacylglycerol transferase Lgt their signal peptides cleaved off by lipoprotein signal peptidase LspA and further triacylated by lipoprotein N acyl transferase Lnt All three enzymes are essential for viability in Gram negative pathogens and their activity is localized to the periplasmic side of the inner membrane indicating that inhibitors will not need to cross the inner membrane Due to the challenges of developing high throughput biochemical screens for these targets and the need for identifying compounds that penetrate bacterial cells target biased whole cell screens were built in A baumannii for both LspA and Lgt inhibitors These consist of A baumannii strains carrying Ptac regulated copies of lgt and lspA in place of the chromosomal copies Both strains cease growth and lose viability as well as cell integrity when IPTG is removed High throughput screens were optimized based on the hypersensitivity of these strains to Lgt and LspA inhibitors in low concentrations of inducer Both assays were validated in pilot screens against known bioactive compounds in duplicate yielding Zandapos factors andgt and hit rates of Moderate throughput cell based and biochemical secondary assays of the Lgt and LspA enzymatic activities were built to validate the target specificity of hits In Phae I the Lgt and LspA HTS assays will be applied to andgt compounds and hits will be confirmed and validated in secondary assays Validated inhibitors will be prioritized by structure and purity dose dependent potency cytotoxicity synergy with existing antibacterials due to cell integrity effects and bacterial spectrum including clinical isolates of P aeruginosa A baumanni and carbapenem resistant K pneumoniae The most potent and selective hits will be prioritized by ADME properties mechanism of action and SAR responsiveness to generate lead compounds In Phase II we will chemically optimize key scaffolds and evaluate their PK toxicity and efficacy in animal infection models to generate preclinical candidates PUBLIC HEALTH RELEVANCE This research is aimed at discovering new drugs that are effective for treating multi drug resistant Gram negative bacterial infections The approach is based on novel cellular assays for inhibitors of two essential bacterial enzymes that have not been exploited previously for new antibiotic discovery The search for new inhibitors of previously unexamined enzymes is likely to provide new chemical structures that are not subject to existing resistance mechanisms and these may be developed into antibiotics for improving therapy of resistant bacteria

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