Entity

Time filter

Source Type

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: | Program: STTR | Phase: Phase I | Award Amount: 300.00K | Year: 2013

DESCRIPTION (provided by applicant): Acinetobacter are strictly aerobic, non-fermentative Gram-negative bacilli that are of major concern in human health, in particular the species Acinetobacter baumannii. They are responsible for clinically important infections that cause a wide variety of maladies including pneumonia, skin and wound infections, bacteremia and meningitis. In addition, A. baumannii biofilms have been implicated in cystic fibrosis, periodontitis and urinary tract infections, due to the bacteria's ability to colonize indwelling medical devices. The rise in antibiotic resistant A. baumannii has severely limited the therapeutic options for treatment, and it is widely recognized that new therapies are desperately needed which is the major goal ofthis STTR. Our laboratories at the University of Pennsylvania and RMH Sciences specialize in targeting the oxidative phosphorylation (OxPhos) system in new antibacterial drug discovery. The OxPhos system is the main pathway used by bacteria to produce energy in the form of ATP and is an essential process for bacterial survival. There are marked differences between the components of the bacterial OxPhos with those of mitochondria and low sequence homology between the two, suggesting that pathogen-specific therapy by this approach is possible. A high throughput screening campaign was conducted to identify A. baumannii OxPhos inhibitors. We have discovered multiple drug-like scaffolds from the HTS that selectively kill A. baumannii, with minimal inhibitory concentration (MIC) values as low as 8 mg/mL. We have identified the target of these compounds to be type 1 NADH dehydrogenase (NDH-1). In this grant, we at the Fox Chase Chemical Diversity Center, Inc. propose in Aim 1 to perform iterative medicinal chemistry to identify compounds with potent and selective antibacterial activity. Medicinal chemistry design is based upon analysis of the top hits from the HTS on which thorough literature review has been conducted, using calculated biophysical properties standard in the industry such as topological polar surface area and Log P as well as considerations of our ability to create new intellectual property. Aim 2 involves iterative in vitr biological testing assays to track biochemical and cellular activity includingsystematic assays to determine the exact molecular basis for the mechanism of action. Importantly, we will confirm the lack of effect in the OxPhos associated with mammalian mitochondria, as already demonstrated for our current hits. In Aim 3, we will utilize standard target validation and hit to lead in vitro and in vivo ADME properties including pharmacokinetic evaluation in mice, and obtain gt3 advanced leads from diverse chemotypes with acceptable ADME and PK properties. Our goal is to produce potent,selective and drug-like advanced leads with MIC values of lt 0.4 mg/mL (lt 0.1 mg/mL preferred). At the completion of this proposal, we will be well suited to transition to Phase II of the STTR program, involving the pre-clinical and clinical developmentactivities required to eventually validate the approach in patients, pursuant to eventual partnering with a major pharmaceutical company and commercialization. PUBLIC HEALTH RELEVANCE PUBLIC HEALTH RELEVANCE: The aim of this proposal is to advance a new class of antibacterial agents to treat Acinetobacter baumannii infections. Over the last 30 years resistance to the drugs used to treat these infections has risen dramatically. New drugs are therefore of urgent need.

Discover hidden collaborations