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DOYLESTOWN, PA, United States

Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase II | Award Amount: 1.00M | Year: 2016

DESCRIPTION provided by applicant Molluscum contagiosum MC is a highly contagious skin disease caused by the poxvirus MCV MC appears as lesions on the body and face and can last months years before resolving Lesions occur most frequently in children and immune compromised individuals The infection is confined to skin alone it is not systemic Transmission spreads directly from person person contact autoinoculation scratching or indirect contact e g towels Current treatments can be painful cause scarring pigmentation and psychological distress especially to children and parents None of the current treatments that include a range of physical chemical and medicinal interventions are uniformly accepted or FDA approved No drug has ever been specifically developed for MC because MCV cannot be grown in any type of cultured cell for the purpose of testing new compounds We have now made FOUR MAJOR BREAKTHROUGHS FIRST we have identified a novel protein target in MCV mD that is essential for viral replication mD is a processivity factor which together with its hetero dimeric partner mA tether the viral Polymerase to the template to enable synthesis of long strands of DNA SECOND we have discovered small molecule inhibitors with different scaffolds that target the mD PF and block long chain DNA synthesis in vitro THIRD we have constructed a new infectious Vaccinia hybrid virus mD VV that expresses the mD target protein and is inhibited from infecting cells by all compounds The mD VV hybrid virus is a major advancement for MC drug development since it provides the first cell based system for screening therapeutics against an essential MCV target protein mD in poxvirus infected cells FOURTH we have now shown the surrogate hybrid virus mD VV can infect D human skin organ cultures equivalent to human skin and that our most potent lead compound has antiviral activity in this system Thus for the first time we have a protein target mD essential for MCV replication a new surrogate hybrid virus for optimizing analogs directed against the mD viral target a natural human D skin organ culture for testing antiviral activity and several compounds with antiviral activity AIMS are tightly interconnected in which medicinal chemistry will be applied in an iterative process to optimize drug efficacy and safety through progressive steps that test for inhibition and binding to the target protein potent antiviral efficacy in cell and human D skin organ cultures skin penetration and safety and efficacy in a cutaneous mouse model of infection with mD VV The specific goal of this Phase II SBIR will be the identification of or more advanced leads suitable for IND enabling studies The ultimate goal of our program is to provide a topical skin formulation that will safely and rapidly resolve MC lesions that occur mainly in children and immune compromised patients PUBLIC HEALTH RELEVANCE Our goal is to develop the first specifically approved drug for treating molluscum contagiosum MC a viral skin disease that afflicts mainly children and immune compromised patients This drug will be for topical use to specifically target the highly contagious MC virus which causes multiple lesions on the skin The MC drug is intended to alleviate the morbidity physical suffering and psychological distress experienced by millions of children and those with impaired immune systems


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase II | Award Amount: 2.31M | Year: 2015

DESCRIPTION provided by applicant The smallpox virus variola has been responsible for the deaths of hundreds of millions of people worldwide Although smallpox was eradicated from the globe in following a valiant immunization campaign existing viral stocks may fall into the hands of those seeking to employ variola as a biological weapon This calls for the development of safe antiviral therapeutics that will protect unvaccinated individuals for the time required to amount an immune response to the vaccine and individuals for whom the vaccine is contraindicated Currently there are two therapeutics brincidofovir and tecovirimat which are in advanced stages of development against smallpox However drug resistant brincidofovir and tecovirimat poxvirus variants arise during infection and site directed alterations of the variola genome could be readily constructed to deliberately engineer poxvirus mutants that are resistant to both drugs Therefore it is important to develop new therapeutics that recognize different poxvirus targets Combinations of new and existing therapeutics will serve to circumvent both the natural and intentional generation of drug resistant variola We have now discovered a platform technology involving small molecules exemplified by a that inhibit infection by vaccinia virus the prototypic poxvirus and causative agent of smallpox Early lead a acts via a novel mechanism in which it binds and destabilizes the vaccinia processivity factor D which is required by the D A processivity heterodimer for tethering the viral polymerase to the DNA template to enable processive or extended strand synthesis Importantly in the case of viral processivity factors there are no cellular homologues making them excellent drug targets Moreover our evidence indicates that early lead a may be broad spectrum for all poxviruses but not for other DNA viruses Our goal is to employ medicinal chemistry to optimize ADMET PK and other properties while retaining improving antiviral potency and creating new composition of matter intellectual property strategically mutate D at structurally defined residues to elucidate its binding mechanism which will also help further guide medicinal chemistry examine the Broad Spectrum potential of our top optimized lead compounds for inhibition of several other poxviruses including monkey pox another bio threat and evaluate the final top optimized compounds for their ability to protec mice against lethal poxvirus challenge By the end of this SBIR Phase II period of study our goal is to have identified one or more preclinical drug candidates with validated antiviral potency and safety ADME PK and other required pharmaceutical criteria prior to conducting the pre clinical development under the Animal Rule required prior to filing an Investigational New Drug IND application with the U S FDA as smallpox countermeasures that may also provide broad spectrum antiviral activity against other poxviruses PUBLIC HEALTH RELEVANCE Smallpox remains a threat to human health either accidentally or by deliberate use such as via bioterrorism We are conducting a systematic program of study to obtain oral therapeutics to treat smallpox acting by a novel mechanism involving blockade of the viral processivity factor D


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 340.00K | Year: 2015

DESCRIPTION provided by applicant We have the discovered the first small molecule probes and drug candidates that effectively inhibit the most prevalent S N drug resistant mutant of the M proton channel of influenza the target of the marketed anti flu drugs amantadine and rimantadine We here propose to exploit our extensive structural biology work in this area to design new related analogs to increase potency for both the most prevalent mutants and wild type M and to understand and improve drug like properties to eventually discover new treatments for seasonal influenza infections Besides the yearly epidemic outbreaks influenza viruses are even more threatening pathogens due to their potency to cause pandemics as occurred in by the emergence and worldwide spread of the H N viruses Available prophylactic vaccines are not completely effective against emerging flu strains thus effective anti viral therapy is not an adjunct but an essential component of our options in the fight against influenza Two classes of drugs are currently approved as antiviral agents the M proton channel inhibitors Symmetrel amantadine and Flumadine rimantadine and the neuraminidase inhibitors Tamiflu oseltamivir and Relenza zanamivir While these drugs are effective in reducing symptomatology from influenza increasing resistance has severely limited their effectiveness Resistance to this class of drugs is associated with naturally occurring point mutations in the M channel pore comprised of a single helical strand through the virus outer coat and four of the M proteins taken together form a functional proton channel The effect of a single mutation is amplified four fold because it is present in all four of the helices that for the pore The S N mutant is the most prevalent and significant amantadine resistant mutation It is present in almost all of the currently circulating influenza strains as well as in the avian nd pandemic H N strains As a result there is an urgent need to develop second generation novel M inhibitors targeting all clinically relevant mutants of M and particularly the most prevalent S N mutant Current efforts have already identified several series of novel and potent in vitro compounds against S N as well as other clinically significant M variants such as V A Our first aim is to optimize the in vitro affinities and drug like properties of the existng series of M S N inhibitors using iterative medicinal chemistry We are uniquely situated to do this based upon our understanding as to the D structure of the pore The second aim is to optimize the in vitro ADME properties of top representative members of different series for in vivo probe and drug like suitability In Phase II we will advance the most promising lead candidates identified in Phase I through pharmacokinetic profiling additional ADME and off target safety studies and animal efficacy and toxicity tests with the ultimate goal of identifying one or more development candidates The long term goal of the program is to complete all studies necessary for filing an Investigational New Drug IND application PUBLIC HEALTH RELEVANCE Seasonal influenza infections as well as the emergence of life threatening strains of influenza are a major worldwide health concern Every year influenza epidemics cause numerous deaths and millions of hospitalizations We are using modern methods of structural biology and medicinal chemistry to discover new small molecule drug candidates that will inhibit not only the influenza wild type M proton channel but also the most prevalent S N and other mutants which are particularly drug resistant to current therapy


Grant
Agency: Department of Health and Human Services | Branch: | Program: STTR | Phase: Phase I | Award Amount: 225.00K | Year: 2014

DESCRIPTION: While HIV/AIDS can be managed with antiretroviral drugs that block viral replication, these agents do not clear the virus and require life-long drug administration with associated risks of cumulative toxicity and drug resistance. Recently, wediscovered a completely new class of compounds that interfere with the HIV-1 virulence factor, Nef. This viral protein is critical to HIV-1 replication in vivo, immune escape of HIV-infected cells, and AIDS progression. Nef antagonists have the potential to synergize with current antiretroviral drugs, thereby reducing toxicities and the risk of drug resistance. Nef inhibitors may also restore immune recognition of HIV-infected cells, potentially clearing the virus. Our lead Nef inhibitors are based on a diphenylpyrazolodiazene (DPP) scaffold that binds directly to the HIV-1 Nef protein and blocks its myriad functions in vitro. The goal of this Phase I STTR grant application, therefore, is to exploit our discovery of novel HIV Nef inhibitors through the


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: STTR | Phase: Phase I | Award Amount: 300.00K | Year: 2015

DESCRIPTION provided by applicant The ultimate goal of this project is to produce a broad spectrum drug for the treatment of viral infections caused by filoviruses Ebola and Marburg arenaviruses Lassa fever and rhabdoviruses rabies We and others have determined that efficient budding of these emerging human pathogens is dependent on the subversion of host proteins such as Nedd and that PPxY late L budding domains expressed by the matrix proteins of these RNA viruses are critical for such interactions As disruption of virus budding would prevent virus dissemination we will evaluate the ability of small molecule inhibitors to disrupt host Nedd viral PPxY interactions thereby preventing virus budding Our collaborators Drs Michael Lee and Mark Olson USAMRIID Ft Detrick MD have used a known protein structure containing a Nedd PPxY interaction to perform an in silico screen to find potential competitive blockers This effort led to an initial active small molecule hit that ws subsequently improved with additional SAR analog testing The goal of this Phase I STTR grant application is to expand this novel finding by designing and preparing additional analogs to understand SAR and initial ADME properties to support a future drug discovery program in Phase II We will accomplish this by combining the pharmaceutical and medicinal chemistry expertise of the Fox Chase Chemical Diversity Center Inc www fc cdci com FCCDC with the expertise and experience of the Harty Lab at the University of Pennsylvania in the clinical and experimental aspects of antiviral therapy In this SAR development proposal we will design and prepare novel analogs suitable for composition of matter intellectual property protection to understand SAR and increase potency in our assays Aim We will use BiMC and VLP budding assays to test analogs for their efficacy at specifically inhibiting the PPxY Nedd interaction and subsequent egress of filovirus particles Aim In this aim we will also test analogs for their ability to block PPxY mediated budding of live viruses including VSV rabies Ebola Kikwit Marburg Ci and Lassa fever We will seek to understand potential drug property issues by obtaining in vitro absorption distribution metabolism and distribution ADME data and pharmacokinetic PK parameters in mice IV administration for advanced lead compounds Aim As L domain containing matrix proteins are required for efficient virus cell separation of many RNA viruses including filoviruses arenaviruses rhabdoviruses paramyxoviruses and henipaviruses we predict that targeting this virus host interaction domain will serve as the basis for the development of new and powerful broad spectrum antiviral drugs Once we achieve the aims of this proposal we will be ideally positioned to transition into a full drug discovery and development program as part of the more extensive STTR Phase II period where we will seek to find one or more PPxY inhibitors to evaluate in detailed IND directed pharmacokinetic pharmacodynamic and toxicity studies PUBLIC HEALTH RELEVANCE There is an urgent need to develop antiviral therapy against emerging human RNA viruses that represent potential agents of bioterrorism Marburg Ebola etc We have discovered small molecule compounds that disrupt virus budding that is critical for virus dissemination and disease progression Here the Harty group at the University of Pennsylvania experts in the antiviral technology of this proposal have partnered with the small business Fox Chase Chemical Diversity Center Inc to further develop these broad spectrum antiviral budding inhibitors by using medicinal chemistry live virus budding assays and live cell imaging techniques

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