Bismaleimide cross ‐linked anthrax toxin forms functional octamers with high specificity in tumor targeting

AbstractIn recent years, anthrax toxin has been reengineered to act as a highly specific antiangiogenic cancer therapeutic, shown to kill tumors in animal models. This has been achieved by modifying protective antigen (PA) so that its activation and toxicity require the presence of two proteases, matrix metalloproteinase (MMP) and urokinase plasminogen activator (uPA), which are upregulated in tumor microenvironments. These therapeutics consist of intercomplementing PA variants, which are individually nontoxic, but form functional toxins upon complementary oligomerization. Here, we have created a dual ‐protease requiring PA targeting system which utilizes bismaleimide cross‐linked PA (CLPA) rather than the intercomplementing PA variants. Three different CLPA agents were tested and, as expected, found to exclusively form octamers. Two of the CLPA agents havein vitro toxicities equal to those of previous intercomplementing agents, while the third CLPA agent had compromisedin vitro cleavage and was significantly less cytotoxic. We hypothesize this difference was due to steric hindrance caused by cross ‐linking two PA monomers in close proximity to the PA cleavage site. Overall, this work advances the development and use of the PA and LF tumor‐targeting system as a practical cancer therapeutic, as it provides a way to reduce the drug components of the anthrax toxin drug delivery system from th ree to two, which may lower the cost and simplify testing in clinical trials.HI...
Source: Protein Science - Category: Biochemistry Authors: Tags: Article Source Type: research

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In conclusion, our study may provide a new theoretical basis for TEM8 application as a clinical biomarker and potential target in EOC patients. PMID: 32774719 [PubMed]
Source: American Journal of Translational Research - Category: Research Tags: Am J Transl Res Source Type: research
The COVID-19 pandemic has had significant global consequences, with healthcare systems stretched to their limits, a growing death toll, and economic devastation as economies came grinding to a halt. The pandemic and its aftereffects will be with u...
Source: Medgadget - Category: Medical Devices Authors: Tags: Exclusive Medicine Public Health Source Type: blogs
I live-tweeted a fascinating and perhaps rather depressing meeting with William Haseltine via a Reuters Newsmaker Broadcast. His talk was upbeat but the message does not offer a positive outlook unless we can collaborate internationally to identify, trace, and isolate and go back to early antivirals to treat people urgently. A vaccine will probably never be found, we must stay on top of this virus when we get communities under control. Moreover, we must recognise that another emergent pathogen could appear any time. These are essentially my notes from Haseltines’s talk. Might we ever achieve herd immunity? There is n...
Source: David Bradley Sciencebase - Songs, Snaps, Science - Category: Science Authors: Tags: Sciencebase Source Type: blogs
I live-tweeted a fascinating and perhaps rather depressing meeting with William Haseltine via a Reuters Newsmaker Broadcast. His talk was upbeat but the message does not offer a positive outlook unless we can collaborate internationally to identify, trace, and isolate and go back to early antivirals to treat people urgently. A vaccine will probably never be found, we must stay on top of this virus when we get communities under control. Moreover, we must recognise that another emergent pathogen could appear any time. These are essentially my notes from Haseltines’s talk. Might we ever achieve herd immunity? There is n...
Source: David Bradley Sciencebase - Songs, Snaps, Science - Category: Science Authors: Tags: Sciencebase Source Type: blogs
ACS Chemical BiologyDOI: 10.1021/acschembio.9b01027
Source: ACS Chemical Biology - Category: Chemistry Authors: Source Type: research
Abstract The non-toxic anthrax protective antigen/lethal factor N-terminal domain (PA/LFN ) complex is an effective platform for translocating proteins into the cytosol of cells. Mutant PA (mPA) was recently fused to epidermal growth factor (EGF) to achieve retargeted delivery of LFN to cells bearing EGF receptors (EGFR), but the requirement of a known cognate ligand limits the applicability of this approach. Here we render practical protective antigen retargeting to a variety of receptors with mPA-single-chain variable fragment (scFv) fusion constructs. Our design enables targeting of two pancreatic cancer-releva...
Source: Chembiochem - Category: Biochemistry Authors: Tags: Chembiochem Source Type: research
Three medical stories that we didn't cover, explained.Medscape
Source: Medscape General Surgery Headlines - Category: Surgery Tags: Internal Medicine Article Source Type: news
Current treatments for bladder cancer need improvement. A new study combines a growth factor with anthrax toxin to create a quick, effective treatment.
Source: Health News from Medical News Today - Category: Consumer Health News Tags: Cancer / Oncology Source Type: news
A combination of anthrax and a growth factor found on the surface of bladder cancer cells allowed Purdue University researchers to target and kill tumors with unprecedented speed.
Source: the Mail online | Health - Category: Consumer Health News Source Type: news
(Purdue University) Researchers at Purdue University have come up with a way to combine the anthrax toxin with a growth factor to kill bladder cancer cells and tumors.
Source: EurekAlert! - Cancer - Category: Cancer & Oncology Source Type: news
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