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AIEA, HI, United States

Johnson A.T.,Hawaii Biotech, Inc.
Journal of Chemical Education | Year: 2015

At present, small molecule drug design follows a retrospective path when considering what analogs are to be made around a current hit or lead molecule with the focus often on identifying a compound with higher intrinsic potency. What this approach overlooks is the simultaneous need to also improve the physicochemical (PC) and pharmacokinetic (PK) properties of these compounds, and illustrates the multivariate problem the chemist must face when targeting new analogs for synthesis. To address this problem, a simple method is presented which allows the chemist to integrate PC properties into small molecule drug design in a prospective manner, prioritize new target molecules for synthesis, and potentially shorten the path to the clinic. This simple method also provides a tool for the student of medicinal chemistry to see how changes in PC properties and intrinsic potency can influence drug-like properties of small molecules during the drug discovery process. © 2014 The American Chemical Society and Division of Chemical Education, Inc. Source


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 2.98M | Year: 2009

DESCRIPTION (provided by applicant): Tick-borne encephalitis (TBE) is a neurological disease caused by Flaviviruses of the tick-borne encephalitis group and causes death in up to 60% of the individuals developing clinical symptoms. Survivors often show severe long-term neurological sequelae. In addition to the classical viruses, the TBE complex of viruses also contains members that cause hemorrhagic fevers sometimes in combination with neurological symptoms. The infection is naturally transmitted via vector ticks in endemic areas. However, the highly infective viruses can also be transmitted via food or in aerosolized form. Therefore, development of a TBE virus vaccine is a NIH high-priority biodefense project (and as such listed in the NIAID Biodefense research agenda for category B and C pathogens. Currently available commercial vaccines based on inactivated whole virus are not registered in the U.S., show considerable vaccination side-effects and are labeled for use only against the less virulent Central European subtype. In the previous phase I SBIR project recombinant TBE subunit proteins were successfully produced in insect cells. The recombinant proteins showed very potent immunogenicity in mice when used with modern adjuvants. The leading formulations showed good efficacy in the mouse challenge models of Western and Far Eastern subtype TBE viruses. In addition, a preliminary study demonstrated that the leading vaccine candidate also confers complete protection against the more distantly related Omsk Hemorrhagic Fever virus. During the phase II project, the antigen manufacturing will be advanced and the necessary quality control steps implemented to progress with the scale-up of production. This will include safety testing of well-defined antigen in a rat toxicology study. Biological and physical assays to evaluate the response to the vaccines will be further developed and standardized. Those assays will be used to document the effect of antigen dosage in the leading vaccine formulation and evaluate the need for a third vaccination to achieve complete protection (in different mouse models). Another study will compare the potency of the recombinant TBE antigen with that of conventionally produced inactivated TBE virus. After refining the vaccine formulation, protective efficacy in mice against the more distant members of the TBE complex will be evaluated. Based on mouse studies the leading candidate will be tested in non-human primates to demonstrate safety and immunogenicity. Efficacy in primates will be demonstrated indirectly using well accepted passive protection studies in mice. The planned studies should complete the pre-clinical efficacy requirements and would therefore be an important step towards the clinical development of a novel TBE vaccine. A safe and efficacious vaccine based on recombinant subunit proteins would provide useful in protecting U.S. citizens from TBEV infection without the need of large-scale culture of highly infectious virus. PUBLIC HEALTH RELEVANCE - PROJECT NARRATIVE: Tick-borne encephalitis (TBE) viruses cause severe neurological disease or hemorrhagic fevers and survivors often show severe long-term neurological sequelae. Currently available commercial vaccines based on inactivated whole virus are not registered in the U.S., show considerable vaccination side-effects and are labeled for use only against the less virulent Central European subtype. This project is aimed to develop a safe and efficacious vaccine formulation based on a recombinant subunit protein which requires only two doses to provide broad protection against all members of the TBE complex to protect U.S. citizens from TBEV infection in endemic areas around the world.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 530.90K | Year: 2012

DESCRIPTION (provided by applicant): Emerging and reemerging infectious diseases continue to pose serious health threats world-wide. Consequently, the development of measures to mitigate the natural, as well as potential bioterrorist threats of these infectious diseases is an important endeavor. The NIAID Strategic Plan for Biodefense Research is specifically directed at promoting research that can provide solutions to mitigate the threat posed by Category A, B, and C priority pathogens. The development ofvaccines against these pathogens provides a strategy to mitigate the potential threat. Crimean-Congo hemorrhagic fever virus (CCHFV) is a significant human pathogen due to it ability cause severe disease and its high fatality rate. CCHFV is classified as acategory C priority pathogen due the concern that it could be used as a biological agent. There is currently no effective vaccine or therapy that is widely available to mitigate such a threat. New technologies and production methods may offer the most effective responses to such disease threats. The proposed research aims to develop a vaccine to protect against disease caused by infection with CCHFV using a stable insect cell line expression platform that has previously been used to produce vaccine candidates for other priority pathogens. The platform is based on the production of recombinant subunit proteins that maintain structural and immunogenic integrity. Candidate vaccines against dengue and West Nile virus have already been produced in this system and both have entered clinical trials. Thus, this platform can be scaled for cGMP production and meet FDA regulatory requirements. The expression of the CCHFV Gn and Gc envelope glycoprotein will be evaluated. The complex nature of viral envelope glycoproteins presents challenges in designing and expressing recombinant subunits that maintain native-like structure. The platform proposed for use in this project has the demonstrated capability of producing complex viral envelope proteins with native-like conformation. Successfully expressed recombinant products will be evaluated for immunogenic potential using two novel adjuvant formulations that have dose sparing potential. Based on immunogenicity studies, selected combinations of recombinant proteins and adjuvant will be evaluated in protective efficacy studies utilizing a recently developed mouse challenge model for CCHFV. In addition to vaccine development, the protein subunits produced can be used for development of diagnostic reagents, as well as targets forantiviral drug development. The successful development of a CCHFV vaccine utilizing this stable insect cell platform will not only meet the need for a safe and effective vaccine against CCHFV, it will also help to demonstrate the utility of the platform and pave the way for the development of additional vaccines against NIAID viral priority pathogens. PUBLIC HEALTH RELEVANCE: The proposed research is focused on the development of a vaccine to protect against disease caused by Crimean-Congo hemorrhagic fever virus (CCHFV), which is a member of the Bunyaviridae family and is the causative agent of a clinical febrile illness with a propensity to cause significant hemorrhagic fever. Due to the hemorrhagic nature of the disease and the high mortality rate, CCHF has been classified as a NIAID category C priority pathogen. Threat of CCHF as an emerging disease continues as the number of cases continues to increase. The development of vaccines against viral diseases on the NIAID priority pathogens list hasproven to be a challenging endeavor. Aside from vaccines for yellow fever and Japanese encephalitis, no other licensed vaccines have been developed for any of the other viral priority pathogens. The proposed work to develop a CCHF vaccine is based on a cell culture expression system that has been demonstrated to be capable of meeting FDA regulatory requirements and producing safe vaccine candidates. The vaccine manufacturing platform is based on the expression of recombinant subunit proteins in stably transformed insect cells. The successful development of a CCHF recombinant subunit vaccine based on this platform supports the concept that a single platform can be utilized to produce vaccines against a number of viral priority pathogens.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 999.98K | Year: 2006

DESCRIPTION (provided by applicant): The strain of West Nile virus now endemic in the continental United States is more virulent than the virus originally isolated in Africa and is classified as a category B priority pathogen by the NIAID. In only six years, it has spread throughout the continental United States, resulting in high morbidity and mortality. Last year, of the 2,539 cases reported to the CDC, nearly half of the patents had neuroinvasive symptoms. There is currently no vaccine or drug that combats the West Nile virus infection and only symptomatic treatment is available. Our ultimate goal is to develop a prophylactic or therapeutic treatment for this disease. To accomplish this, we will develop methods for the identification of compounds that inhibit the West Nile viral NS3 protease. The protease is a key enzyme in viral maturation and inhibition of flavivirus protease has been shown to dramatically reduce viral replication. Structure based drug design will provide a rapid path to potent and virus specific protease inhibitors. The crystal structure of this protease in the presence and absence of known peptide based inhibitors will be determined in an effort to characterize the active site. We will virtually screen the active site with a chemical library. Careful attention will be made to the composition of the library to ensure enrichment with diverse, pharmacologically active, lead-like compounds. A biochemical assay will be developed that has a wide range of sensitivity that can be used in the identification of weak binding initial hits from our virtual screen as well as to measure small changes in inhibition as we optimize these hits in future research. Compounds that are selected in the virtual screen and are active in the biochemical assay will be cocrystallized with the protease, giving us a clear picture of the compound's fit into the active site. This will position us to rapidly identify the best candidates from the active compounds and subsequent optimization in phase 2 research.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 797.65K | Year: 2006

DESCRIPTION (provided by applicant): Over half of the world population is at risk for infection by dengue virus, a mosquito borne member of the Flavivirus family that consists of four distinct serotypes. Approximately 50 to 100 million infections occur annually resulting in an estimated 500,000 cases of life threatening dengue hemorrhagic fever or dengue shock syndrome. Due to the increased incidence and spreading geographic distribution of dengue infection, it is considered to be an emerging disease and is identified by NIAID as a category A priority pathogen. Despite the significant disease burden associated with dengue infection there is presently no approved vaccine or antiviral drug. The goal of this project is to discover and develop antiviral drugs that inhibit dengue virus infection by blocking the cell entry step in the virus life cycle. Dengue infection of host cells is mediated by the envelope protein, a class II viral fusion protein responsible for virus attachment and for triggering fusion between the virus and host cell membranes. Hawaii Biotech has expressed the envelope proteins of dengue virus in purified native form. The 3-dimensional structures of the dengue-2 envelope protein in both a pre and a post fusion state have recently been solved as a collaborative project with Stephen Harrison's laboratory at Harvard Medical School. The structures reveal two potential drug target sites on the envelope protein for inhibitors of the fusion process. One target is a hydrophobic pocket present in the native envelope of the virus particle, and the other is a channel present in the fusion intermediate form of the protein involved in the late stages of membrane fusion. These targets will be examined by molecular modeling through a process of virtual drug screening to find potential inhibitor compounds that will then be tested experimentally. The purified envelope protein undergoes the conformational rearrangements of the fusion process in vitro under appropriate conditions. This will form the basis for development of fluorescence based assay methods that can be used to identify fusion inhibitors. A cell based assay for dengue envelope mediated membrane fusion will also be developed for testing of inhibitor candidates. By evaluating two distinct molecular targets that represent different stages in the fusion process, and by exploring several different assay designs, we intend to be in a position at the conclusion of Phase I to select the best path to discovery of effective antiviral drugs for dengue and other Flaviviruses during Phase II.

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