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  1. Article ; Online: Pharmacology of a Plant Virus Immunotherapy Candidate for Peritoneal Metastatic Ovarian Cancer.

    Omole, Anthony O / Affonso de Oliveira, Jessica Fernanda / Sutorus, Lucas / Steinmetz, Nicole F

    ACS pharmacology & translational science

    2024  Volume 7, Issue 2, Page(s) 445–455

    Abstract: Due to the increasing incidence of cancer, there is a need to develop new platforms that can combat this disease. Cancer immunotherapy is a platform that takes advantage of the immune system to recognize and eradicate tumors and metastases. Our lab has ... ...

    Abstract Due to the increasing incidence of cancer, there is a need to develop new platforms that can combat this disease. Cancer immunotherapy is a platform that takes advantage of the immune system to recognize and eradicate tumors and metastases. Our lab has identified a plant virus nanoparticle, cowpea mosaic virus (CPMV) as a promising approach for cancer immunotherapy. When administered intratumorally, CPMV relieves the immune system of tumor-induced immunosuppression and reprograms the tumor microenvironment into an activated state to launch systemic antitumor immunity. The efficacy of CPMV has been tested in many tumor models and in canine cancer patients with promising results: tumor shrinkage, systemic efficacy (abscopal effect), and immune memory to prevent recurrence. To translate this drug candidate from the bench to the clinic, studies that investigate the safety, pharmacology, and toxicity are needed. In this work, we describe the efficacy of CPMV against a metastatic ovarian tumor model and investigate the biodistribution of CPMV after single or repeated intraperitoneal administration in tumor-bearing and healthy mice. CPMV shows good retention in the tumor nodules and broad bioavailability with no apparent organ toxicity based on histopathology. Data indicate persistence of the viral RNA, which remains detectable 2 weeks post final administration, a phenomenon also observed with some mammalian viral infections. Lastly, while protein was not detected in stool or urine, RNA was shed through excretion from mice; however, there was no evidence that RNA was infectious to plants. Taken together, the data indicate that systemic administration results in broad bioavailability with no apparent toxicity. While RNA is shed from the subjects, data suggest agronomical safety. This data is consistent with prior reports and provides support for translational efforts.
    Language English
    Publishing date 2024-01-10
    Publishing country United States
    Document type Journal Article
    ISSN 2575-9108
    ISSN (online) 2575-9108
    DOI 10.1021/acsptsci.3c00285
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Systemic Administration of Cowpea Mosaic Virus Demonstrates Broad Protection Against Metastatic Cancers.

    Chung, Young Hun / Zhao, Zhongchao / Jung, Eunkyeong / Omole, Anthony O / Wang, Hanyang / Sutorus, Lucas / Steinmetz, Nicole F

    Advanced science (Weinheim, Baden-Wurttemberg, Germany)

    2024  , Page(s) e2308237

    Abstract: The key challenge in cancer treatment is prevention of metastatic disease which is therapeutically resistant and carries poor prognoses necessitating efficacious prophylactic approaches that prevent metastasis and recurrence. It is previously ... ...

    Abstract The key challenge in cancer treatment is prevention of metastatic disease which is therapeutically resistant and carries poor prognoses necessitating efficacious prophylactic approaches that prevent metastasis and recurrence. It is previously demonstrated that cowpea mosaic virus (CPMV) induces durable antitumor responses when used in situ, i.e., intratumoral injection. As a new direction, it is showed that CPMV demonstrates widespread effectiveness as an immunoprophylactic agent - potent efficacy is demonstrated in four metastatic models of colon, ovarian, melanoma, and breast cancer. Systemic administration of CPMV stimulates the innate immune system, enabling attack of cancer cells; processing of the cancer cells and associated antigens leads to systemic, durable, and adaptive antitumor immunity. Overall, CPMV demonstrated broad efficacy as an immunoprophylactic agent in the rejection of metastatic cancer.
    Language English
    Publishing date 2024-03-02
    Publishing country Germany
    Document type Journal Article
    ZDB-ID 2808093-2
    ISSN 2198-3844 ; 2198-3844
    ISSN (online) 2198-3844
    ISSN 2198-3844
    DOI 10.1002/advs.202308237
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: In Vivo Fate of Cowpea Mosaic Virus In Situ Vaccine: Biodistribution and Clearance.

    Affonso de Oliveira, Jessica Fernanda / Chan, Soo Khim / Omole, Anthony O / Agrawal, Vanshika / Steinmetz, Nicole F

    ACS nano

    2022  Volume 16, Issue 11, Page(s) 18315–18328

    Abstract: Cowpea mosaic virus (CPMV) is a nucleoprotein nanoparticle that functions as a highly potent immunomodulator when administered intratumorally and is used as an in situ vaccine. CPMV in situ vaccination remodels the tumor microenvironment and primes a ... ...

    Abstract Cowpea mosaic virus (CPMV) is a nucleoprotein nanoparticle that functions as a highly potent immunomodulator when administered intratumorally and is used as an in situ vaccine. CPMV in situ vaccination remodels the tumor microenvironment and primes a highly potent, systemic, and durable antitumor immune response against the treated and untreated, distant metastatic sites (abscopal effect). Potent efficacy was demonstrated in multiple tumor mouse models and, most importantly, in canine cancer patients with spontaneous tumors. Data indicate that presence of anti-CPMV antibodies are not neutralizing and that in fact opsonization leads to enhanced efficacy. Plant viruses are part of the food chain, but to date, there is no information on human exposure to CPMV. Therefore, patient sera were tested for the presence of immunoglobulins against CPMV, and indeed, >50% of deidentified patient samples tested positive for CPMV antibodies. To get a broader sense of plant virus exposure and immunogenicity in humans, we also tested sera for antibodies against tobacco mosaic virus (>90% patients tested positive), potato virus X (<20% patients tested positive), and cowpea chlorotic mottle virus (no antibodies were detected). Further, patient sera were analyzed for the presence of antibodies against the coliphage Qβ, a platform technology currently undergoing clinical trials for in situ vaccination; we found that 60% of patients present with anti-Qβ antibodies. Thus, data indicate human exposure to CPMV and other plant viruses and phages. Next, we thought to address agronomical safety; i.e., we examined the fate of CPMV after intratumoral treatment and oral gavage (to mimic consumption by food). Because live CPMV is used, an important question is whether there is any evidence of shedding of infectious particles from mice or patients. CPMV is noninfectious toward mammals; however, it is infectious toward plants including black-eyed peas and other legumes. Biodistribution data in tumor-bearing and healthy mice indicate little leaching from tumors and clearance via the reticuloendothelial system followed by biliary excretion. While there was evidence of shedding of RNA in stool, there was no evidence of infectious particles when plants were challenged with stool extracts, thus indicating agronomical safety. Together these data aid the translational development of CPMV as a drug candidate for cancer immunotherapy.
    MeSH term(s) Humans ; Animals ; Dogs ; Mice ; Comovirus ; Tissue Distribution ; Cancer Vaccines ; Immunotherapy ; Kinetics ; Antibodies ; Mammals
    Chemical Substances Cancer Vaccines ; Antibodies
    Language English
    Publishing date 2022-10-20
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ISSN 1936-086X
    ISSN (online) 1936-086X
    DOI 10.1021/acsnano.2c06143
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article: Chemical tools to define and manipulate interferon-inducible Ubl protease USP18.

    Davis, Griffin J / Omole, Anthony O / Jung, Yejin / Rut, Wioletta / Holewinski, Ronald / Suazo, Kiall F / Kim, Hong-Rae / Yang, Mo / Andresson, Thorkell / Drag, Marcin / Yoo, Euna

    bioRxiv : the preprint server for biology

    2024  

    Abstract: Ubiquitin-specific protease 18 (USP18) is a multifunctional cysteine protease primarily responsible for deconjugating interferon-inducible ubiquitin-like (Ubl) modifier ISG15 from protein substrates. Here, we report the design and synthesis of activity- ... ...

    Abstract Ubiquitin-specific protease 18 (USP18) is a multifunctional cysteine protease primarily responsible for deconjugating interferon-inducible ubiquitin-like (Ubl) modifier ISG15 from protein substrates. Here, we report the design and synthesis of activity-based probes (ABPs) capable of selectively detecting USP18 activity over other ISG15 cross-reactive deubiquitinases (DUBs) by incorporating unnatural amino acids into the C-terminal tail of ISG15. Combining with a ubiquitin-based DUB ABP, the selective USP18 ABP is employed in a chemoproteomic screening platform to identify and assess inhibitors of DUBs including USP18. We further demonstrate that USP18 ABPs can be utilized to profile differential activities of USP18 in lung cancer cell lines, providing a strategy that will help define the activity-related landscape of USP18 in different disease states and unravel important (de)ISGylation-dependent biological processes.
    Language English
    Publishing date 2024-04-08
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2024.04.08.588544
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article: Preparation of Bioderived and Biodegradable Surfactants Based on an Intrinsically Disordered Protein Sequence

    Klass, Sarah H. / Gleason, Jamie M. / Omole, Anthony O. / Onoa, Bibiana / Bustamante, Carlos J. / Francis, Matthew B.

    Biomacromolecules. 2022 Mar. 03, v. 23, no. 3

    2022  

    Abstract: Surfactants, block copolymers, and other types of micellar systems are used in a wide variety of biomedical and industrial processes. However, most commonly used surfactants are synthetically derived and pose environmental and toxicological concerns ... ...

    Abstract Surfactants, block copolymers, and other types of micellar systems are used in a wide variety of biomedical and industrial processes. However, most commonly used surfactants are synthetically derived and pose environmental and toxicological concerns throughout their product life cycle. Because of this, bioderived and biodegradable surfactants are promising alternatives. For biosurfactants to be implemented industrially, they need to be produced on a large scale and also have tailorable properties that match those afforded by the polymerization of synthetic surfactants. In this paper, a scalable and versatile production method for biosurfactants based on a hydrophilic intrinsically disordered protein (IDP) sequence with a genetically engineered hydrophobic domain is used to study variables that impact their physicochemical and self-assembling properties. These amphiphilic sequences were found to self-assemble into micelles over a broad range of temperatures, pH values, and ionic strengths. To investigate the role of the IDP hydrophilic domain on self-assembly, variants with increased overall charges and systematically decreased IDP domain lengths were produced and examined for their sizes, morphologies, and critical micelle concentrations (CMCs). The results of these studies indicate that decreasing the length of the IDP domain and consequently the molecular weight and hydrophilic fraction leads to smaller micelles. In addition, significantly increasing the amount of charged residues in the hydrophilic IDP domain results in micelles of similar sizes but with higher CMC values. This represents an initial step in developing a quantitative model for the future engineering of biosurfactants based on this IDP sequence.
    Keywords amino acid sequences ; biodegradability ; biosurfactants ; composite polymers ; hydrophilicity ; hydrophobicity ; micelles ; models ; molecular weight ; pH ; polymerization ; product life cycle ; toxicology
    Language English
    Dates of publication 2022-0303
    Size p. 1462-1470.
    Publishing place American Chemical Society
    Document type Article
    ISSN 1526-4602
    DOI 10.1021/acs.biomac.2c00051
    Database NAL-Catalogue (AGRICOLA)

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  6. Article ; Online: Preparation of Bioderived and Biodegradable Surfactants Based on an Intrinsically Disordered Protein Sequence.

    Klass, Sarah H / Gleason, Jamie M / Omole, Anthony O / Onoa, Bibiana / Bustamante, Carlos J / Francis, Matthew B

    Biomacromolecules

    2022  Volume 23, Issue 3, Page(s) 1462–1470

    Abstract: Surfactants, block copolymers, and other types of micellar systems are used in a wide variety of biomedical and industrial processes. However, most commonly used surfactants are synthetically derived and pose environmental and toxicological concerns ... ...

    Abstract Surfactants, block copolymers, and other types of micellar systems are used in a wide variety of biomedical and industrial processes. However, most commonly used surfactants are synthetically derived and pose environmental and toxicological concerns throughout their product life cycle. Because of this, bioderived and biodegradable surfactants are promising alternatives. For biosurfactants to be implemented industrially, they need to be produced on a large scale and also have tailorable properties that match those afforded by the polymerization of synthetic surfactants. In this paper, a scalable and versatile production method for biosurfactants based on a hydrophilic intrinsically disordered protein (IDP) sequence with a genetically engineered hydrophobic domain is used to study variables that impact their physicochemical and self-assembling properties. These amphiphilic sequences were found to self-assemble into micelles over a broad range of temperatures, pH values, and ionic strengths. To investigate the role of the IDP hydrophilic domain on self-assembly, variants with increased overall charges and systematically decreased IDP domain lengths were produced and examined for their sizes, morphologies, and critical micelle concentrations (CMCs). The results of these studies indicate that decreasing the length of the IDP domain and consequently the molecular weight and hydrophilic fraction leads to smaller micelles. In addition, significantly increasing the amount of charged residues in the hydrophilic IDP domain results in micelles of similar sizes but with higher CMC values. This represents an initial step in developing a quantitative model for the future engineering of biosurfactants based on this IDP sequence.
    MeSH term(s) Hydrophobic and Hydrophilic Interactions ; Inosine Diphosphate ; Intrinsically Disordered Proteins ; Micelles ; Surface-Active Agents/chemistry
    Chemical Substances Intrinsically Disordered Proteins ; Micelles ; Surface-Active Agents ; Inosine Diphosphate (86-04-4)
    Language English
    Publishing date 2022-03-03
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ISSN 1526-4602
    ISSN (online) 1526-4602
    DOI 10.1021/acs.biomac.2c00051
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Self-Assembling Micelles Based on an Intrinsically Disordered Protein Domain.

    Klass, Sarah H / Smith, Matthew J / Fiala, Tahoe A / Lee, Jess P / Omole, Anthony O / Han, Bong-Gyoon / Downing, Kenneth H / Kumar, Sanjay / Francis, Matthew B

    Journal of the American Chemical Society

    2019  Volume 141, Issue 10, Page(s) 4291–4299

    Abstract: The self-assembly of micellar structures from diblock polymers that contain hydrophilic and hydrophobic domains has been of great interest for the encapsulation of drugs and other hydrophobic molecules. While most commercially used surfactants are ... ...

    Abstract The self-assembly of micellar structures from diblock polymers that contain hydrophilic and hydrophobic domains has been of great interest for the encapsulation of drugs and other hydrophobic molecules. While most commercially used surfactants are derived from hydrocarbon sources, there have been recent efforts to replace these with biodegradable, nontoxic, biologically synthesized alternatives. Previous examples have primarily examined naturally occurring self-assembling proteins, such as silk and elastin-like sequences. Herein, we describe a new series of fusion proteins that have been developed to self-assemble spontaneously into stable micelles that are 27 nm in diameter after enzymatic cleavage of a solubilizing protein tag. The sequences of the proteins are based on a human intrinsically disordered protein, which has been appended with a hydrophobic segment. The micelles were found to form across a broad range of pH, ionic strength, and temperature conditions, with critical micelle concentration (CMC) values in the low micromolar range, 3 orders of magnitude lower than the CMC of commonly used surfactant sodium dodecyl sulfate (SDS). The reported micelles were found to solubilize hydrophobic metal complexes and organic molecules, suggesting their potential suitability for catalysis and drug delivery applications. Furthermore, the inherent flexibility in the design of these protein sequences enables the encoding of additional functionalities for many future applications. Overall, this work represents a new biomolecular alternative to traditional surfactants that are based on nonrenewable and poorly biodegradable hydrocarbon sources.
    MeSH term(s) Amino Acid Sequence ; Antifungal Agents/chemistry ; Escherichia coli/genetics ; Hydrogen-Ion Concentration ; Hydrophobic and Hydrophilic Interactions ; Intrinsically Disordered Proteins/chemistry ; Intrinsically Disordered Proteins/genetics ; Micelles ; Photosensitizing Agents/chemistry ; Porphyrins/chemistry ; Protein Domains ; Protein Engineering ; Recombinant Fusion Proteins/chemistry ; Recombinant Fusion Proteins/genetics ; Solubility ; Strobilurins/chemistry ; Temperature
    Chemical Substances 5,10,15,20-tetraphenylporphyrin ; Antifungal Agents ; Intrinsically Disordered Proteins ; Micelles ; Photosensitizing Agents ; Porphyrins ; Recombinant Fusion Proteins ; Strobilurins ; pyrachlostrobin (DJW8M9OX1H)
    Language English
    Publishing date 2019-02-26
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S. ; Video-Audio Media
    ZDB-ID 3155-0
    ISSN 1520-5126 ; 0002-7863
    ISSN (online) 1520-5126
    ISSN 0002-7863
    DOI 10.1021/jacs.8b10688
    Database MEDical Literature Analysis and Retrieval System OnLINE

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