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Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: STTR | Phase: Phase I | Award Amount: 597.06K | 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 The current ongoing Ebola epidemic in West Africa has led to more than deaths and underscores the global challenge of treating and controlling this deadly virus This application defines a plan to identify and develop potent small molecule inhibitors which block entry of EBOV into host cells We have developed a cell based HTS protocol targeting Ebola entry to identify small molecule inhibitors that block entry of infectious EBOV The overall objective of this Phase I application is to identify and develop these inhibitors as potential anti Ebola therapeutics This application will focus on the following three specific aims Identify potent anti Ebola inhibitors from a small molecule library of GPCR antagonists prioritize and chemically modify the most potent inhibitors 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 inhibitors Select EBOV 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 viral infection The proposed research will help to develop potential antivira therapeutics


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

Novel compounds are disclosed having the structure of Formula I: 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: 300.00K | Year: 2016

Human respiratory syncytial virus hRSV and human metapneumovirus hMPV are non segmented negative strand viruses NNSV and are the leading causes of acute respiratory tract infections in infants worldwide In addition hRSV is a significant cause of disease in elderly populations and can often be fatal for patients with compromised immune systems Currently no vaccines are available and existing therapeutics e g ribavirin immunoglobulin or anti hRSV monoclonal Synagis exhibit poor efficacy and present safety concerns The development of safer more effective therapeutics is a major unmet medical need The goal of this project is to address this need by discovering and developing inhibitors of hRSV and hMPV RNA synthesis for therapeutic use by targeting the interaction between the viral nucleoprotein N and the viral P protein a cofactor for the viral polymerase L This interaction is critical for viral RNA synthesis in cells infected with NNSVs an L N complex is required for replication and P mediates interactions between L and the N RNA template The strategy is to build and apply biochemical screens for inhibitors of the hRSV and hMPV N P interaction based on fluorescence polarization This approach is based on a successful anti Ebola virus screening effort carried out by this team to identify inhibitors of the interaction between the Ebola nucleoprotein eNP and the Ebola P protein equivalent known as eVP Development and application of a primary fluorescence polarization assay FPA followed by secondary assays including a counter screen FPA based on an unrelated interaction resulted in the discovery of six specific eVP eNP interaction inhibitors with IC values ranging from M to M Two of these compounds inhibited Ebola RNA synthesis in a cell based assay known as a minigenome replication assay In Phase I these efforts will be extended to target this conserved viral interaction by focusing on hRSV and hMPV which are of broad clinical importance Primary FPA screens for inhibitors of the hRSV and hMPV N protein interactions with fluorophore labeled peptides from the corresponding P proteins will be developed In addition biochemical e g biolayer interferometry BLI and cellular e g split luciferase secondary assays with orthogonal read outs will be constructed to validate initial hits and to assess cellular permeability and mechanism of action The primary and secondary assays will be applied to andgt diverse compounds Confirmed potent selective inhibitors will be validated by determining their ability to inhibit infectious viral assays and by ensuring that they are not cytotoxic In vitro ADME assays and preliminary SAR will prioritize analogs for further optimization Strengths of this proposal include the productive collaborative research team highly sensitive homogeneous FPA screens FPA counter screens to rapidly recognize and eliminate false positives potential to identify broad inhibitors targeting hRSV and hMPV and cellular assays to establish the target specific function In Phase II priority validated inhibitors will be chemically optimized into lead compounds for efficacy and toxicity testing in animal models Narrative Human respiratory syncytial virus hRSV and human metapneumovirus hMPV are the leading causes of acute respiratory tract infections in infants worldwide Currently no vaccines are available and existing therapeutics exhibit poor efficacy and present safety concerns The goal of this proposal is to discover and develop novel safe inhibitors of hRSV and hMPV RNA synthesis for therapeutic use by targeting the interaction between the viral nucleoprotein N and the viral P protein a cofactor for the viral polymerase L This interaction is critical for viral RNA synthesis and viral replication


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: STTR | Phase: Phase I | Award Amount: 302.98K | Year: 2016

DESCRIPTION provided by applicant The inability to treat many Gram negative bacterial infections effectively with existing antibiotics is a major medical crisis Pseudomonas aeruginosa is a prime example of clinical isolates from critically ill patients are resistant to three or more drugs The overall goal of this project is to address the critical medical need by a novel approach of identifying specific inhibitors of the type three secretion system T SS targeting the extracellular T SS needle and developing them into novel therapeutic agents against P aeruginosa T SS is the major virulence factor contributing to the establishment and dissemination of P aeruginosa infections and is utilized by the bacterium to secrete and translocate toxin effectors into host phagocytes and weaken the hostandapos s innate immune response The presence of a functional T SS is significantly associated with poor clinical outcomes and death in patients and markedly reduces survival in animal infection models T SS inhibitors will be administered therapeutically and prophylactically in combination with anti pseudomonal agents to inhibit the T SS potentiate a robust host innate immune response and enhance the antibacterial activity of co administered antibiotics The strategy is to identify and optimize small molecules that interfere with the extracellular T SS needle polymerization or stability Such therapeutics will by pass P aeruginosa intrinsic resistance mechanisms caused by a poorly permeable outer membrane and efflux pumps Preliminary studies revealed a putative binding site for the phenoxyacetamide series of T SS inhibitors in the polymeric form of the needle protein PscF indicating that the needle is a target of the P aeruginosa T SS for small molecule inhibition The strategy of screening directly for compounds that alter the needle assembly or stability will capitalize on this newfound vulnerability and provide additional chemotypes of needle inhibitors for the drug development pipeline In other preliminary studies we developed methods for the purification of PscF and demonstrated a fluorescence based assay to monitor the polymerization of a purified T SS needle protein In Phase I a high throughput screen using purified PscF will be developed optimized and implemented to identify small molecules that inhibit needle polymerization or stability Diverse compound libraries will be screened and resulting andapos hitsandapos will be confirmed in the screening assay in replicate prioritized b potency and selectivity by eliminating compounds that alter actin polymerization or stability or are promiscuous in multiple screens Confirmed potent selective andapos hitsandapos will be validated as T SS inhibitors by determining their ability to inhibit effector secretion and translocation from P aeruginosa and by ensuring that they are not cytotoxic do not disrupt mammalian cell membranes and do not affect bacterial growth or viability in vitro Preliminary SAR and in vitro ADME assays and will be used to prioritize analogs In Phase II the most promising of these T SS inhibitors will be optimized to develop lead compounds for efficacy and toxicity testing in animal models PUBLIC HEALTH RELEVANCE The increasing prevalence of antibiotic resistant strains of Pseudomonas aeruginosa is dire threat to the health of infected patients and represents an unmet medical need These bacteria are resistant to many drugs because of a thick outer membrane and efflux pumps and they weaken the patientandapos s innate immune cellular response by injecting toxins into the cells through a type three secretion system T SS Successful development of an inhibitor targeting the extracellular needle of this T SS virulence mechanism will provide a new weapon to combat acute infections such as pneumonia and bacteremia


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 569.84K | Year: 2015

DESCRIPTION provided by applicant The overall goal of this project is to address the critical medical need for agents to combat antibacterial drug resistance by a novel approach of potentiating drug influx in Gram negative non fermenters such as Pseudomonas aeruginosa and Acinetobacter baumannii These species exhibit intrinsic drug resistance due to the combined effects of a poorly permeable outer membrane and several multi drug efflux pumps The approach of this project is to develop novel adjunctive therapeutics to increase the intracellular effective levels of new and existing antibiotics The OprF OmpA family of porins in P aeruginosa and A baumannii appears to be the major route for influx of many existing antibiotics and likely for many new antibacterial since these porins are the major route for non specific diffusion of drug sized molecules across the outer membrane However these porins exist predominately in a two domain closed channel form which spans the outer membrane and peptidoglycan layer to stabilize the cell structure The low levels of one domain open channel conformers reduce the outer membrane permeability by one to two orders of magnitude as compared to that of enterobacteriaciae such as Escherichia coli The strategy of this proposal is to identify drug like small molecules that shift the balance towards the open channel porin conformer thus improving antibacterial influx by opening the porin and destabilizing the bacterial cell structure The two conformations are not in rapid equilibrium but appear to result from a structure based bias for the two domain closed channel from in the folding pathway of nascent proteins Preliminary studies established that several specific mutations in P aeruginosa OprF shift the ratio toward the open channel form and that a cysteine created at residue in a form of OprF devoid of other cysteines is exposed on the cell surface only when OprF porins are in the single domain open channel form Labeling cys with a fluorescent membrane impermeable dye provides an assay to detect and quantify open channel forms In Phase I development and optimization of the assay will be completed to enable high throughput screening to identify small molecules that significantly shift the folding pathway toward open channel conformers The optimized screen will be applied to a diverse library of discrete small molecules Hits will be selected and confirmed in the screening assay and then validated for specificity and concentration dependent potency in secondary assays including osmotic swelling rates of proteoliposomes containing OprF in the presence of L arabinose OprF protease sensitivity and reduced MICs for cephalosporins in P aeruginosa Resulting non cytotoxic validated hits will be prioritized by their extent of potentiation of the MICs of a variety of antibacterials vs multiple P aeruginosa and A baumannii clinical isolates as well as related species such as Burkholderia cepacia and Stenotrophomonas maltophilia In Phase II the most promising of these influx facilitators will be optimized to develop lead compounds for efficacy and toxicity testing in animal models PUBLIC HEALTH RELEVANCE The increasing prevalence of antibiotic resistant strains of bacterial pathogens represents an unmet medical need Development of new adjunctive agents that facilitate the influx of antibiotics into poorly permeable Gram negative bacteria will potentiate the activity of existing and new antibiotics Successful development of an influx facilitator will help combat acute infections such as pneumonia and bacteremia


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase II | Award Amount: 1.74M | Year: 2015

DESCRIPTION provided by applicant Multi drug resistance MDR in Gram negative pathogens including the Enterobacteriaceae and Pseudomonas aeruginosa poses a significant threat to our ability to effectively treat infections caused by these organisms A major component in the development of the MDR phenotype in Gram negative bacteria is overexpression of RND type efflux pumps which actively pump antibacterial agents and biocides from the periplasm to the outside of the cell Clearly bacterial efflux pumps are an important target for developing novel antibacterial treatments that increase the potency of existing antibiotics and decrease the emergence of MDR bacteria In preliminary studies we identified a novel pyranopyridine MBX that is a potent inhibitor of AcrAB TolC the major efflux pump of E coli and other Enterobacteriaceae MBX enhances the activity of fluoroquinolones FQs and lactam antibiotics against E coli but does not exhibit antibacterial activity alone nor is it cytotoxic In Phase I we synthesized MBX analogs and evaluated them for potency selectivity spectrum of activity and in vitro ADME properties to identify compounds with improved activity and drug like properties and to generate a molecular activity map for this series As a result of this research we have identified analogs that exhibit a andgt fold increase in antibiotic potentiation and satisfy the criteria for successful completion of the Phase I milestones The overall goal of this Phase II project is to further develop the pyranopyridine series to identify in vivo validated lead compounds that are suitable for IND enabling preclinical studies In Phase II we will utilize an approach that combines structure based drug design with medicinal chemistry to design and synthesize analogs with improved spectrum of activity and ADMET properties while maintaining potency against efflux by the Enterobacteriaceae To facilitate this approach and probe the mechanism of action we will generate a three dimensional structure of MBX and analogs bound to AcrB Analogs will be evaluated in a panel of secondary assays to prioritize compounds for efficacy and pharmacokinetic PK studies in animals In addition the data derived from these assays will inform the design of additional compounds Through an iterative process of compound design and evaluation we anticipate that we will identify in vivo validated lead compounds with favorable PK and in vivo efficacy In Phase III these efflux pump inhibitors will be developed for use in combination with levofloxacin LEV or piperacillin tazobactam PIP TAZ as an adjunctive therapy for urinary tract and bloodstream infections as the first therapeutic indications for this inhibitor series These adjunctive therapis represent a significant improvement over single agent therapies because they will provide the following benefits increased antibiotic efficacy at lower concentrations and decreased evolution of resistance The Specific Aims for Phase II are as follows Aim Chemically optimize the pyranopyridine series to generate lead compounds for animal safety and efficacy testing Aim Prioritize analogs by potency spectrum selectivity favorable in vitro ADMET properties Aim Determine the three dimensional structure of pyranopyridines bound to AcrB and biochemical mechanism Aim Evaluate acute toxicity pharmacokinetics and efficacy of lead compounds in animal models PUBLIC HEALTH RELEVANCE The AcrAB TolC efflux pump plays an important role in the intrinsic resistance of many important bacterial pathogens to many of the antibiotics that are used to treat infections caused by these organisms Increased production of this efflux pump can result in multidrug resistance MDR Inhibition of this efflux pump will result in increased efficacy of antibiotic therapies and decreased evolution of resistance In this project we will develop a series of novel efflux pump inhibitors the pyranopyridines to show in vivo efficacy with the ultimate goal of developing a novel class of drugs that can be used in combination with existing antibiotics to increase their clinical efficacy in the treatment of Gram negative infectios


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase II | Award Amount: 1.33M | Year: 2015

DESCRIPTION provided by applicant The overall objective of this project is to generate new potent selective antimalarials that act through a novel mechanism of blocking the plasmodial surface anion channel PSAC a previously unexploited and highly conserved plasmodial target Human malaria is caused by five species of protozoan parasites in the genus Plasmodium It is estimated that there are more than million clinical cases of P falciparum malaria and over deaths annually with ninety percent of the deaths occurring in sub Saharan Africa The malaria parasites most importantly P falciparum require two hosts which are humans and female Anopheles mosquitoes Disease is transmitted to humans from the bite of an infected mosquito There are no effective vaccines available to prevent malaria but several small molecule treatment options exist such as chloroquine CQ and artemisinin CQ once the mainstay of malaria treatment has lost much of its efficacy because of mutations that confer resistance Resistance to artemisinin based therapy is now appearing in Southeast Asia New small molecule drugs especially those working on new targets that may be less susceptible to acquired resistance are desperately needed PSAC is a newly discovered essential antimalarial target which was recently validated by gene identification experiments The channel is produced by the parasite and inserts into the infected erythrocyte membrane It was demonstrated by Dr Sanjay Desai NIH that PSAC inhibitors discovered by high throughput screening kill parasites by direct action on this channel In preliminary studies Dr Desai developed and applied a screen for PSAC inhibitors using a sorbitol transport assay which resulted in the identification of several chemotypes that displayed inhibitory potencies K PSAC block in the nanomolar range Compounds also inhibited plasmodial growth with low nanomolar potencies IC Two of the andquot hit compoundandquot chemical scaffolds were chosen for medicinal chemistry optimization on the basis of their potency low cytotoxicity tractability of synthesis and overall favorable in vitro andquot drug likeandquot ADME results The first MBX was subjected to SAR evaluation in a Phase I SBIR project Compounds in this series demonstrated efficacy low toxicity and excellent in vitro ADME properties The Phase II project proposed here will focus on lead optimizing and scale up chemistry further mechanism of action studies and then in vivo pharmacokinetics and toxicology studies in preparation for efficacy testing We will test the efficacy of prioritized compounds in the humanized SCID mouse model to be conducted by Medicines for Malaria Venture MMV In Phase III we will conduct IND enabling preclinical studies to advance several of the most potent and least toxic compounds from the MBX scaffold The interdisciplinary approach which will merge the antimalarial expertise of Dr Desai and Dr Jeremy Burrows of MMV with the anti infective research and development capabilities of Microbiotix will produce inhibitors for a newly discovered essential and conserved malarial target and provide new treatment options for resistant infections PUBLIC HEALTH RELEVANCE Human malarial disease caused by parasites of the genus Plasmodium afflicts million and causes death in over people per year Although there are drugs available to treat the disease resistance is rapidly eroding their efficacy We propose to develop new antimalarial therapeutic agents that target an unexploited malarial anion channel protein to combat the growing resistance problem


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


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


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 304.39K | Year: 2016

DESCRIPTION provided by applicant Ebola virus EBOV is a member of the filovirus family that causes severe viral hemorrhagic fever VHF Although infrequent epidemics of EBOV can cause high mortality rates of up to the subsequent medical and social upheaval can be widespread and severe as seen in the recent outbreak in Western Africa which has already caused more than fatalities in a region with insubstantial medical services Although some success using monoclonal and polyclonal antibodies has been reported these expensive treatments are not widely available to poorer regions of Africa without substantial assistance from America and Europe additionally it would be beneficial to have the ability to stockpile treatments in case of future outbreaks or bioterrorism This option is not easily achieved with antibody therapies A pressing need for small molecule therapeutics is thus quite evident The experimental drugs brincidofovir favipiravir and BCX have shown promise in vitro but no clinical trials have proven their effectiveness in vivo To address this critical unmet medical need new small molecule therapeutics prophylactics are necessary to avert the risk of future epidemics Using a pseudotype virus that mimics the viral entry process of EBOV we have identified a novel set of small molecule EBOV entry inhibitors that has been validated in assays of infectious EBOV in vitro Based on a beta lactam central core these compounds are readily modified are drug like and represent an excellent starting point for medicinal chemistry optimization By synthesizing new analogs of the hit compound MBX we will generate structure activity relationships to better understand the chemical features that lead to potent anti EBOV activity and low cytotoxicity and ultimately produce potent selective inhibitors of infectious EBOV that display drug like characteristics The current proposal will use medicinal chemistry to optimize MBX using three aims We will synthesize novel analogs of MBX and assay the antiviral activity in a pseudotype assay of EBOV infection We will validate the results of the pseudotype assay using infectious EBOV under BSL conditions We will measure in vitro ADME predictors to improve the overall drug likeness of the scaffold Using an iterative process of compound design synthesis and biological assay we will synthesize optimized compounds that are potent selective and have drug like properties suitable for further development as therapeutics and or prophylactics for EBOV infection PUBLIC HEALTH RELEVANCE This proposal is designed to optimize a series of compounds based on a beta lactam core for use as inhibitors of Ebola virus infection The compounds are an excellent starting point for medicinal chemistry because they are small drug like and readily modified By synthesizing new compounds testing their biological activity against an EBOV pseudotype virus rVSV EBOV and infectious EBOV measuring predictive in vitro ADME predictors and using that information to further improve the design and synthesis of subsequent inhibitors we will synthesize novel small molecule EBOV inhibitors that will have a high probability of succeeding in preclinical development en route to an effective therapeutic for EBOV infections

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