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.
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 979.91K | Year: 2005
DESCRIPTION (provided by applicant): Current influenza vaccine production procedures (use of embryonated chicken eggs) inherently limit the amount of influenza vaccine that can be produced prior to each year's flu season. Most of the influenza vaccine sold is inactivated. Inactivation of the virus is accomplished through the use of agents such as formalin which is a compound that is known to cross-link protein and damage epitopes. There is a clear need for new technologies that can be used to respond quickly to influenza outbreaks and pandemics and produce sufficient doses of high quality vaccine for the U.S. population. There is also need for improved vaccine formulations with increased immunogenicity and efficacy. The overall goal of this research proposal is to evaluate recombinant subunit proteins of the avian influenza strain A/Hong Kong/156/97 (H5N1) as vaccine candidates. Recombinant subunits of the HA, NP and M1 proteins will be expressed in the Drosophila S2 expression system. The recombinantly expressed HA, NP and M1 proteins will be highly purified by column chromatography. The quality of the Drosophila and Bomftyx-expressed proteins is anticipated to be superior to conventionally produced influenza proteins due to the fact that the protein will not be altered by formalin or other agents used for inactivation which can cross-link proteins and destroy epitopes. The subunit proteins will be purified and tested in different combinations as vaccine immunogens in a mouse immunogenicity model. The proteins will also be expressed in the Bombyx mori system to provide Hawaii Biotech Inc an alternative expression system to the Drosophila system. Humoral and cellular immune responses will be evaluated in the mouse model. Dose ranging studies and different adjuvants will also be evaluated. The Drosophila and Bombyx mori expressed HA proteins will be compared to commercially available baculovirus expressed HA protein in the mouse immunogenicity model. Specific optimized vaccine formulations will then be evaluated in a mouse challenge model. In addition, the role of NP and M1 proteins in cellular immune responses will be explored.
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.
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 5.05M | Year: 2004
DESCRIPTION (provided by applicant): West Nile virus infection is an emerging infectious disease in the United States. The virus infects birds, which serve as the natural reservoir for the virus, in addition to humans and horses which are incidental h
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.