- Platform to Discover Protease-Activated Antibiotics and Application to Siderophore-Antibiotic Conjugates
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Here we present a platform for discovery of protease-activated prodrugs and apply it to antibiotics that target Gram-negative bacteria. Because cleavable linkers for prodrugs had not been developed for bacterial proteases, we used substrate phage to discover substrates for proteases found in the bacterial periplasm. Rather than focusing on a single protease, we used a periplasmic extract of E. coli to find sequences with the greatest susceptibility to the endogenous mixture of periplasmic proteases. Using a fluorescence assay, candidate sequences were evaluated to identify substrates that release native amine-containing payloads. We next designed conjugates consisting of (1) an N-terminal siderophore to facilitate uptake, (2) a protease-cleavable linker, and (3) an amine-containing antibiotic. Using this strategy, we converted daptomycin - which by itself is active only against Gram-positive bacteria - into an antibiotic capable of targeting Gram-negative Acinetobacter species. We similarly demonstrated siderophore-facilitated delivery of oxazolidinone and macrolide antibiotics into a number of Gram-negative species. These results illustrate this platform's utility for development of protease-activated prodrugs, including Trojan horse antibiotics.
- Boyce, Jonathan H.,Dang, Bobo,Ary, Beatrice,Edmondson, Quinn,Craik, Charles S.,Degrado, William F.,Seiple, Ian B.
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p. 21310 - 21321
(2021/01/11)
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- CHELATING PLATFORM FOR DELIVERY OF RADIONUCLIDES
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Siderocalin-metal chelator combinations that bind metallic radioisotopes used in nuclear medicine with high affinity are described. The high affinity siderocalin-metal chelator combinations include a number of chelator backbone arrangements with functional groups that coordinate with metals. The siderocalin-metal chelator combinations can be used to deliver radionuclides for imaging and therapeutic purposes.
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- Engineered recognition of tetravalent zirconium and thorium by chelator-protein systems: Toward flexible radiotherapy and imaging platforms
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Targeted α therapy holds tremendous potential as a cancer treatment: it offers the possibility of delivering a highly cytotoxic dose to targeted cells while minimizing damage to surrounding healthy tissue. The metallic α-generating radioisotopes 225Ac and 227Th are promising radionuclides for therapeutic use, provided adequate chelation and targeting. Here we demonstrate a new chelating platform composed of a multidentate high-affinity oxygen-donating ligand 3,4,3-LI(CAM) bound to the mammalian protein siderocalin. Respective stability constants log β110 = 29.65 ± 0.65, 57.26 ± 0.20, and 47.71 ± 0.08, determined for the EuIII (a lanthanide surrogate for AcIII), ZrIV, and ThIV complexes of 3,4,3-LI(CAM) through spectrophotometric titrations, reveal this ligand to be one of the most powerful chelators for both trivalent and tetravalent metal ions at physiological pH. The resulting metal-ligand complexes are also recognized with extremely high affinity by the siderophore-binding protein siderocalin, with dissociation constants below 40 nM and tight electrostatic interactions, as evidenced by X-ray structures of the protein:ligand:metal adducts with ZrIV and ThIV. Finally, differences in biodistribution profiles between free and siderocalin-bound 238PuIV-3,4,3-LI(CAM) complexes confirm in vivo stability of the protein construct. The siderocalin:3,4,3-LI(CAM) assembly can therefore serve as a "lock" to consolidate binding to the therapeutic 225Ac and 227Th isotopes or to the positron emission tomography emitter 89Zr, independent of metal valence state.
- Captain, Ilya,Deblonde, Gauthier J.-P.,Rupert, Peter B.,An, Dahlia D.,Illy, Marie-Claire,Rostan, Emeline,Ralston, Corie Y.,Strong, Roland K.,Abergel, Rebecca J.
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p. 11930 - 11936
(2016/12/03)
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- Diphenyl-benzo[1,3]dioxole-4-carboxylic acid pentafluorophenyl ester: A convenient catechol precursor in the synthesis of siderophore vectors suitable for antibiotic Trojan horse strategies
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Catechols are components of many metal-chelating compounds, including siderophores that are naturally occurring iron(iii) chelators excreted by microorganisms. Catechol derivatives are poorly soluble in organic media and the synthesis of catechol-containing molecules requires the use of protected catechol precursors with improved organic solubility. We therefore developed 2,2-diphenyl-benzo[1,3]dioxole-4-carboxylic acid pentafluorophenyl ester. This activated ester reacts with an amine functionalized scaffold to generate chelators in which the catechol functions are protected in the form of diphenyl-benzodioxole moieties. The catechol can subsequently be deprotected, at the end of the synthesis, with trifluoroacetic acid (TFA). This strategy was applied to the synthesis of two catechol compounds functionalized with a terminal propargyl extension. These two compounds were shown to promote iron uptake in Escherichia coli and Pseudomonas aeruginosa. These two compounds are suitable for use as vectors in antibiotic Trojan horse approaches, as they could be conjugated with azide-functionalized antibiotics using the Huisgen dipolar 1,3-cycloaddition.
- Baco, Etienne,Hoegy, Francoise,Schalk, Isabelle J.,Mislin, Gaetan L. A.
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p. 749 - 757
(2014/01/23)
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- New COMT inhibitors for the treatment of depression and impaired cognition
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The present invention relates to compounds of formula I wherein R1 is as defined in the specification and to esters thereof which are hydrolyzable under physiological conditions and to the pharmaceutically acceptable salts thereof. The compounds of the invention are inhibitors of COMT and, thus, are useful for the treatment of diseases for which COMT inhibition is beneficial. The invention further relates to the treatment, control, or prevention of diseases such as depression, schizophrenia, Parkinson's disease, and to improve cognition.
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Page/Page column 6
(2010/02/12)
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- Secondary β-Aminobenzamide and Heteroatom Directed Lithiation in the Synthesis of 5,6-Dimethoxyanthanilamides and Related Compounds
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Directed ortho-lithiation strategies have been applied in the synthesis of the dopamine D-2 antagonist (S)-6-amino-5-bromo-2,3-dimethoxy-N-benzamide (NCQ 318).The secondary β-amino side chain was found to be a powerful orth
- Bengtsson, Stefan,Hoegberg, Thomas
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p. 4549 - 4553
(2007/10/02)
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- New Polycyclic β-Lactams. Synthesis of 2a,3-Dihydroazetoquinoline-1,4(2H)-diones, Structural Analogues of the Carbacephalosporin Antibiotics
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A method has been developed for the preparation of dihydroxydihydroazetoquinoline-1,4(2H)-diones (1).The synthesis involved, as a key step, the completion of the polycyclic β-lactam system by a modified Bischler-Napieralski reaction.It was illustrated by the synthesis of (+/-)-7,8-dihydroxy-3,3-dimethyl-2-phenoxyacetamido-2a,3-dihydroazetoquinoline-1,4(2H)-dione (20), which is structurally related to the carbacephalosporin antibiotics.
- Bachi, Mario D.,Klein, Joseph
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p. 1925 - 1928
(2007/10/02)
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