PanThera Biopharma LLC

‘Aiea, HI, United States

PanThera Biopharma LLC

‘Aiea, HI, United States
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Lehrer A.T.,PanThera Biopharma LLC | Lehrer A.T.,University of Hawaii at Manoa | Wong T.A.S.,PanThera Biopharma LLC | Wong T.A.S.,University of Hawaii at Manoa | And 9 more authors.
Vaccine | Year: 2017

Infections with filoviruses in humans are highly virulent, causing hemorrhagic fevers which result in up to 90% mortality. In addition to natural infections, the ability to use these viruses as bioterrorist weapons is of significant concern. Currently, there are no licensed vaccines or therapeutics available to combat these infections. The pathogenesis of disease involves the dysregulation of the host's immune system, which results in impairment of the innate and adaptive immune responses, with subsequent development of lymphopenia, thrombocytopenia, hemorrhage, and death. Questions remain with regard to the few survivors of infection, who manage to mount an effective adaptive immune response. These questions concern the humoral and cellular components of this response, and whether such a response can be elicited by an appropriate prophylactic vaccine. The data reported herein describe the production and evaluation of a recombinant subunit Ebola virus vaccine candidate consisting of insect cell expressed Zaire ebolavirus (EBOV) surface glycoprotein (GP) and the matrix proteins VP24 and VP40. The recombinant subunit proteins are shown to be highly immunogenic in mice, yielding both humoral and cellular responses, as well as highly efficacious, providing up to 100% protection against a lethal challenge with live virus. These results demonstrate proof of concept for such a recombinant non-replicating vaccine candidate in the mouse model of EBOV which helps to elucidate immune correlates of protection and warrants further development. © 2017 Elsevier Ltd.

Jiao G.-S.,PanThera Biopharma LLC | Kim S.,PanThera Biopharma LLC | Moayeri M.,National Institute of Allergy and Infectious Diseases | Crown D.,National Institute of Allergy and Infectious Diseases | And 10 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2012

Four core structures capable of providing sub-nanomolar inhibitors of anthrax lethal factor (LF) were evaluated by comparing the potential for toxicity, physicochemical properties, in vitro ADME profiles, and relative efficacy in a rat lethal toxin (LT) model of LF intoxication. Poor efficacy in the rat LT model exhibited by the phenoxyacetic acid series (3) correlated with low rat microsome and plasma stability. Specific molecular interactions contributing to the high affinity of inhibitors with a secondary amine in the C2-side chain were revealed by X-ray crystallography. © 2011 Elsevier Ltd. All rights reserved.

Jiao G.-S.,PanThera Biopharma LLC | Kim S.,PanThera Biopharma LLC | Moayeri M.,National Institute of Allergy and Infectious Diseases | Cregar-Hernandez L.,PanThera Biopharma LLC | And 4 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2010

Sub-nanomolar small molecule inhibitors of anthrax lethal factor have been identified using SAR and Merck L915 (4) as a model compound. One of these compounds (16) provided 100% protection in a rat lethal toxin model of anthrax disease. © 2010 Elsevier Ltd. All rights reserved.

Moayeri M.,National Institute of Allergy and Infectious Diseases | Crown D.,National Institute of Allergy and Infectious Diseases | Jiao G.-S.,PanTheraBiopharma LLC | Kim S.,PanTheraBiopharma LLC | And 3 more authors.
Antimicrobial Agents and Chemotherapy | Year: 2013

Bacillus anthracis, the causative agent of anthrax, manifests its pathogenesis through the action of two secreted toxins. The bipartite lethal and edema toxins, a combination of lethal factor or edema factor with the protein protective antigen, are important virulence factors for this bacterium. We previously developed small-molecule inhibitors of lethal factor proteolytic activity (LFIs) and demonstrated their in vivo efficacy in a rat lethal toxin challenge model. In this work, we show that these LFIs protect against lethality caused by anthrax infection in mice when combined with subprotective doses of either antibiotics or neutralizing monoclonal antibodies that target edema factor. Significantly, these inhibitors provided protection against lethal infection when administered as a monotherapy. As little as two doses (10 mg/kg) administered at 2 h and 8 h after spore infection was sufficient to provide a significant survival benefit in infected mice. Administration of LFIs early in the infection was found to inhibit dissemination of vegetative bacteria to the organs in the first 32 h following infection. In addition, neutralizing antibodies against edema factor also inhibited bacterial dissemination with similar efficacy. Together, our findings confirm the important roles that both anthrax toxins play in establishing anthrax infection and demonstrate the potential for small-molecule therapeutics targeting these proteins. Copyright © 2013, American Society for Microbiology. All Rights Reserved.

Kim S.,PanThera Biopharma LLC | Jiao G.-S.,PanThera Biopharma LLC | Moayeri M.,National Institute of Allergy and Infectious Diseases | Crown D.,National Institute of Allergy and Infectious Diseases | And 5 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2011

New anthrax lethal factor inhibitors (LFIs) were designed based upon previously identified potent inhibitors 1a and 2. Combining the new core structures with modifications to the C2-side chain yielded analogs with improved efficacy in the rat lethal toxin model. © 2011 Elsevier Ltd. All rights reserved.

Jarvi S.I.,University of Hawaii at Hilo | Hu D.,Hawaii Pacific Islands Cooperative Ecosystems Studies Unit | Misajon K.,National Park Service | Coller B.-A.,Hawaii Biotech, Inc. | And 4 more authors.
Journal of Wildlife Diseases | Year: 2013

Although West Nile Virus (WNV) has not been reported in Hawai'i, eventual introduction appears unavoidable with potential adverse effects on avian species. Nēnē (Branta sandvicensis) are endemic endangered Hawaiian geese that are susceptible to WNV. We demonstrate that a vaccine developed against WNV for humans (WN-80E) is also highly immunogenic in Nēnē and does not produce adverse biologic effects. Six captive, nonbreeding Nēnē were immunized with two 10-mg doses (4 wk apart) of the WN-80E recombinant protein adjuvanted with Montanide ISA720. Two Nēnē were similarly injected with "mock" preparation as controls. Blood samples were collected before the first dose, then 2 wk and 6 mo after the second dose. WNV-specific antibody titers were determined by an endpoint enzyme-linked immunosorbent assay. An unpaired t-test demonstrated significantly higher geometric mean titers for immunized vs. control groups 2 wk after dose 2 (4,129 and 100, respectively, P=0.010) and 6 mo after dose 2 (246 and 63, respectively, P=0.002). Daily observations revealed no swelling at the site of injection and no serious adverse biological effects from the immunization. The vaccine containing the WN-80E and Montanide ISA720 adjuvant appears to be safe and immunogenic in Nēnē. This protein-based WNV vaccine may be safer for use in Hawai'i than killed virus and live chimeric or recombinant canarypox-vectored vaccines because it cannot cause disease. © Wildlife Disease Association 2013.

Cregar-Hernandez L.,PanThera Biopharma LLC | Jiao G.-S.,PanThera Biopharma LLC | Johnson A.T.,PanThera Biopharma LLC | Lehrer A.T.,PanThera Biopharma LLC | And 2 more authors.
Antiviral Chemistry and Chemotherapy | Year: 2011

Background: Dengue fever, dengue haemorrhagic fever, and dengue shock syndrome are caused by infections with any of the four serotypes of the dengue virus (DENV), and are an increasing global health risk. The related West Nile virus (WNV) causes significant morbidity and mortality as well, and continues to be a threat in endemic areas. Currently no FDA-approved vaccines or therapeutics are available to prevent or treat any of these infections. Like the other members of Flaviviridae, DENV and WNV encode a protease (NS3) which is essential for viral replication and therefore is a promising target for developing therapies to treat dengue and West Nile infections. Methods: Flaviviral protease inhibitors were identified and biologically characterized for mechanism of inhibition and DENV antiviral activity.Results: A guanidinylated 2,5-dideoxystreptamine class of compounds was identified that competitively inhibited the NS3 protease from DENV(1-4) and WNV with 50% inhibitory concentration values in the 1-70 μM range. Cytotoxicity was low; however, antiviral activity versus DENV-2 on VERO cells was not detectable. Conclusions: This class of compounds is the first to demonstrate competitive pan-dengue and WNV NS3 protease inhibition and, given the sequence conservation among flavivirus NS3 proteins, suggests that developing a pan-dengue or possibly pan-flavivirus therapeutic is feasible. ©2011 International Medical Press.

O'Malley S.,PanThera Biopharma LLC | Sareth S.,PanThera Biopharma LLC | Jiao G.-S.,PanThera Biopharma LLC | Kim S.,PanThera Biopharma LLC | And 5 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2013

A novel method for applying high-throughput docking to challenging metalloenzyme targets is described. The method utilizes information-based virtual transformation of library carboxylates to hydroxamic acids prior to docking, followed by compound acquisition, one-pot (two steps) chemical synthesis and in vitro screening. In two experiments targeting the botulinum neurotoxin serotype A metalloprotease light chain, hit rates of 32% and 18% were observed. © 2013 Elsevier Ltd. All rights reserved.

Thompson A.A.,Scripps Research Institute | Jiao G.-S.,PanThera Biopharma LLC | Kim S.,PanThera Biopharma LLC | Thai A.,PanThera Biopharma LLC | And 6 more authors.
Biochemistry | Year: 2011

Neurotoxins synthesized by Clostridium botulinum bacteria (BoNT), the etiological agent of human botulism, are extremely toxic proteins making them high-risk agents for bioterrorism. Small molecule inhibitor development has been focused on the light chain zinc-dependent metalloprotease domain of the neurotoxin, an effort that has been hampered by its relatively flexible active site. Developed in concert with structure-activity relationship studies, the X-ray crystal structures of the complex of BoNT serotype A light chain (BoNT/A LC) with three different micromolar-potency hydroxamate-based inhibitors are reported here. Comparison with an unliganded BoNT/A LC structure reveals significant changes in the active site as a result of binding by the unique inhibitor scaffolds. The 60/70 loop at the opening of the active site pocket undergoes the largest conformational change, presumably through an induced-fit mechanism, resulting in the most compact catalytic pocket observed in all known BoNT/A LC structures. © 2011 American Chemical Society.

PanThera Biopharma LLC | Date: 2011-04-04

Filovirus subunit protein immunogens are produced using a recombinant expression system and combined with one or more adjuvants in immunogenic formulations. The subunit proteins include GP95, GP-FL, VP40, VP24, and NP derived from Ebola Virus and Marburg Virus. Adjuvants include saponins, emulsions, alum, and dipeptidyl peptidase inhibitors. The disclosed immunogenic formulations are effective in inducing strong antibody responses directed against individual Filovirus proteins and intact Filovirus particles as well as stimulating cell-mediated immune responses to the Filoviruses.

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