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1.
bioRxiv ; 2024 May 23.
Article in English | MEDLINE | ID: mdl-38826442

ABSTRACT

Maintaining safe and potent pharmaceutical drug levels is often challenging. Multidomain peptides (MDPs) assemble into supramolecular hydrogels with a well-defined, highly porous nanostructure that makes them attractive for drug delivery, yet their ability to extend release is typically limited by rapid drug diffusion. To overcome this challenge, we developed self-assembling boronate ester release (SABER) MDPs capable of engaging in dynamic covalent bonding with payloads containing boronic acids (BAs). As examples, we demonstrate that SABER hydrogels can prolong the release of five BA-containing small-molecule drugs as well as BA-modified insulin and antibodies. Pharmacokinetic studies revealed that SABER hydrogels extended the therapeutic effect of ganfeborole from days to weeks, preventing Mycobacterium tuberculosis growth better than repeated oral administration in an infection model. Similarly, SABER hydrogels extended insulin activity, maintaining normoglycemia for six days in diabetic mice after a single injection. These results suggest that SABER hydrogels present broad potential for clinical translation.

2.
Angew Chem Int Ed Engl ; : e202405344, 2024 May 16.
Article in English | MEDLINE | ID: mdl-38753429

ABSTRACT

Peptide cyclization has dramatic effects on a variety of important properties, enhancing metabolic stability, limiting conformational flexibility, and altering cellular entry and intracellular localization. The hydrophilic, polyfunctional nature of peptides creates chemoselectivity challenges in macrocyclization, especially for natural sequences without biorthogonal handles. Herein, we describe a gaseous sulfonyl chloride-derived reagent that achieves amine-amine, amine-phenol, and amine-aniline crosslinking via a minimalist linchpin strategy that affords macrocyclic urea or carbamate products. The cyclization reaction is metal-mediated, and involves a novel application of sulfine species that remains unexplored in aqueous or biological contexts. The aqueous method delivers unique cyclic or bicyclic topologies directly from a variety of natural bioactive peptides without the need for protecting-group strategies.

3.
Bioconjug Chem ; 2024 May 13.
Article in English | MEDLINE | ID: mdl-38739108

ABSTRACT

Hybrid materials that combine organic polymers and biomacromolecules offer unique opportunities for precisely controlling 3D chemical environments. Although biological or organic templates have been separately used to control the growth of inorganic nanoclusters, hybrid structures represent a relatively unexplored approach to tailoring nanocluster properties. Here, we demonstrate that a molecularly defined lysozyme-polymer resin material acts as a structural scaffold for the synthesis of copper nanoclusters (CuNCs) with well controlled size distributions. The resulting CuNCs have significantly enhanced fluorescence compared with syntheses based on polymeric or biological templates alone. The synergistic approach described here is appealing for the synthesis of biocompatible fluorescent labels with improved photostability.

4.
Chem Commun (Camb) ; 59(87): 13030-13033, 2023 Oct 31.
Article in English | MEDLINE | ID: mdl-37842954

ABSTRACT

Proximity-induced methodologies for peptide and protein modification have been developed using recognition elements like inhibitors, antibodies, or affinity tags on amino acids. However, the recognition of saccharides for chemical modification remains widely unexplored. Studies exploring boronic acids and their derivatives have shown their alluring capabilities as selective molecular recognition elements for saccharides, and in this study we describe the application of these ideas to the discovery of a catalytic proximity-induced methodology for covalent modification of glycopeptides using boronic acids as a saccharide recognition element.


Subject(s)
Rhodium , Rhodium/chemistry , Boronic Acids/chemistry , Peptides/chemistry , Carbohydrates , Catalysis
5.
ACS Appl Mater Interfaces ; 15(39): 45601-45605, 2023 Oct 04.
Article in English | MEDLINE | ID: mdl-37724983

ABSTRACT

Low-temperature plasma is an emerging approach for the treatment of bacterial infections. Nonchemical treatments such as cold plasma offer potential solutions to antibiotic resistance. We investigated the use of laser-induced graphene as an inexpensive, lightweight, and portable electrode for generating cold plasma. At the same time, the mechanism or molecular mediators of cold plasma-induced antibacterial activity remain poorly understood. This study validates graphene as an efficient structure for producing therapeutic cold plasma, and this study also indicates that ozone is the primary mediator of antibacterial activity in graphene-mediated cold plasmas for bacterial growth under the conditions studied.

6.
Biomacromolecules ; 24(5): 2196-2202, 2023 05 08.
Article in English | MEDLINE | ID: mdl-37084390

ABSTRACT

The use of transition-metal-mediated boronic acid chemistry presents a novel method of protein immobilization on a solid support. This is a one-step method that site-selectively immobilizes pyroglutamate-histidine (pGH)-tagged proteins. Herein, we describe the synthesis of alkenylboronic acid-functionalized poly(ethylene glycol) acrylamide (PEGA) resin and its subsequent reactions with pGH-tagged proteins to produce covalent linkages. The selectivity of immobilization is demonstrated within fluorescent studies, model mixtures, and lysates.


Subject(s)
Boronic Acids , Transition Elements , Proteins , Polyethylene Glycols , Indicators and Reagents
7.
Cancers (Basel) ; 15(4)2023 Feb 20.
Article in English | MEDLINE | ID: mdl-36831684

ABSTRACT

Survival of pediatric AML remains poor despite maximized myelosuppressive therapy. The pneumocystis jiroveci pneumonia (PJP)-treating medication atovaquone (AQ) suppresses oxidative phosphorylation (OXPHOS) and reduces AML burden in patient-derived xenograft (PDX) mouse models, making it an ideal concomitant AML therapy. Poor palatability and limited product formulations have historically limited routine use of AQ in pediatric AML patients. Patients with de novo AML were enrolled at two hospitals. Daily AQ at established PJP dosing was combined with standard AML therapy, based on the Medical Research Council backbone. AQ compliance, adverse events (AEs), ease of administration score (scale: 1 (very difficult)-5 (very easy)) and blood/marrow pharmacokinetics (PK) were collected during Induction 1. Correlative studies assessed AQ-induced apoptosis and effects on OXPHOS. PDX models were treated with AQ. A total of 26 patients enrolled (ages 7.2 months-19.7 years, median 12 years); 24 were evaluable. A total of 14 (58%) and 19 (79%) evaluable patients achieved plasma concentrations above the known anti-leukemia concentration (>10 µM) by day 11 and at the end of Induction, respectively. Seven (29%) patients achieved adequate concentrations for PJP prophylaxis (>40 µM). Mean ease of administration score was 3.8. Correlative studies with AQ in patient samples demonstrated robust apoptosis, OXPHOS suppression, and prolonged survival in PDX models. Combining AQ with chemotherapy for AML appears feasible and safe in pediatric patients during Induction 1 and shows single-agent anti-leukemic effects in PDX models. AQ appears to be an ideal concomitant AML therapeutic but may require intra-patient dose adjustment to achieve concentrations sufficient for PJP prophylaxis.

8.
Chem Sci ; 13(47): 14101-14105, 2022 Dec 07.
Article in English | MEDLINE | ID: mdl-36540816

ABSTRACT

Sulfoximines are emerging moieties for medicinal and biological chemistry, due in part to their efficacy in selective inhibition of amide-forming enzymes such as γ-glutamylcysteine synthetase. While small-molecule sulfoximines such as methionine sulfoximine (MSO) and its derivatives are well studied, structures with methionine sulfoximine residues within complex polypeptides have been generally inaccessible. This paper describes a straightforward means of late-stage one-step oxidation of methionine residues within polypeptides to afford NH-sulfoximines. We also present chemoselective subsequent elaboration, most notably by copper(ii)-mediated N-H cross-coupling at methionine sulfoximine residues with arylboronic acid reagents. This development serves as a strategy to incorporate diverse sulfoximine structures within natural polypeptides, and also identifies the methionine sulfoximine residue as a new site for bioorthogonal, chemoselective bioconjugation.

9.
Bioconjug Chem ; 33(12): 2307-2313, 2022 12 21.
Article in English | MEDLINE | ID: mdl-36445785

ABSTRACT

Boronic acids and boronate esters find appreciable use in chemical biology. Molecules containing orthogonal boronic acid pairs can be utilized for sequential metal-catalyzed cross-couplings for facile preparation of complex bioconjugates including protein-protein conjugates. In this paper, we expand bis-boronic acid reagents for tandem covalent and dynamic bioconjugation. Sequential cross-coupling of 2-nitroarylboronic acid with cysteine residues and condensation of phenylboronic acid with salicylhydroxamic acids (SHA) readily afforded bioconjugates under physiological conditions with dual covalent and dynamic linkages. Both small molecule- and macromolecule-protein conjugates were amenable with this approach and reversible upon addition of excess unfunctionalized SHA or reactive oxygen species. These investigations provide new insights into the kinetic stability of SHA adducts.


Subject(s)
Boronic Acids , Proteins , Indicators and Reagents , Boronic Acids/chemistry , Esters/chemistry , Macromolecular Substances
10.
JCI Insight ; 7(3)2022 02 08.
Article in English | MEDLINE | ID: mdl-35132956

ABSTRACT

Acute respiratory distress syndrome (ARDS) results in catastrophic lung failure and has an urgent, unmet need for improved early recognition and therapeutic development. Neutrophil influx is a hallmark of ARDS and is associated with the release of tissue-destructive immune effectors, such as matrix metalloproteinases (MMPs) and membrane-anchored metalloproteinase disintegrins (ADAMs). Here, we observed using intravital microscopy that Adam8-/- mice had impaired neutrophil transmigration. In mouse pneumonia models, both genetic deletion and pharmacologic inhibition of ADAM8 attenuated neutrophil infiltration and lung injury while improving bacterial containment. Unexpectedly, the alterations of neutrophil function were not attributable to impaired proteolysis but resulted from reduced intracellular interactions of ADAM8 with the actin-based motor molecule Myosin1f that suppressed neutrophil motility. In 2 ARDS cohorts, we analyzed lung fluid proteolytic signatures and identified that ADAM8 activity was positively correlated with disease severity. We propose that in acute inflammatory lung diseases such as pneumonia and ARDS, ADAM8 inhibition might allow fine-tuning of neutrophil responses for therapeutic gain.


Subject(s)
ADAM Proteins/genetics , Antigens, CD/genetics , Gene Expression Regulation , Membrane Proteins/genetics , RNA/genetics , Respiratory Distress Syndrome/genetics , ADAM Proteins/biosynthesis , Animals , Antigens, CD/biosynthesis , Cells, Cultured , Disease Models, Animal , Humans , Male , Membrane Proteins/biosynthesis , Mice , Mice, Inbred C57BL , Microscopy, Confocal , Respiratory Distress Syndrome/metabolism , Respiratory Distress Syndrome/pathology
11.
Beilstein J Org Chem ; 17: 2932-2938, 2021.
Article in English | MEDLINE | ID: mdl-34956413

ABSTRACT

Photo-responsive modifications and photo-uncaging concepts are useful for spatiotemporal control of peptides structure and function. While side chain photo-responsive modifications are relatively common, access to photo-responsive modifications of backbone N-H bonds is quite limited. This letter describes a new photocleavage pathway, affording N-formyl amides from vinylogous nitroaryl precursors under physiologically relevant conditions via a formal oxidative C=C cleavage. The N-formyl amide products have unique properties and reactivity, but are difficult or impossible to access by traditional synthetic approaches.

12.
Bioconjug Chem ; 32(9): 1947-1959, 2021 09 15.
Article in English | MEDLINE | ID: mdl-34428033

ABSTRACT

Antibodies, particularly of the immunoglobulin G (IgG) isotype, are a group of biomolecules that are extensively used as affinity reagents for many applications in research, disease diagnostics, and therapy. Most of these applications require antibodies to be modified with specific functional moieties, including fluorophores, drugs, and proteins. Thus, a variety of methodologies have been developed for the covalent labeling of antibodies. The most common methods stably attach functional molecules to lysine or cysteine residues, which unavoidably results in heterogeneous products that cannot be further purified. In an effort to prepare homogeneous antibody conjugates, bioorthogonal handles have been site-specifically introduced via enzymatic treatment, genetic code expansion, or genetically encoded tagging, followed by functionalization using bioorthogonal conjugation reactions. The resulting homogeneous products have proven superior to their heterogeneous counterparts for both in vitro and in vivo usage. Nevertheless, additional chemical treatment or protein engineering of antibodies is required for incorporation of the bioorthogonal handles, processes that often affect antibody folding, stability, and/or production yield and cost. Accordingly, concurrent with advances in the fields of bioorthogonal chemistry and protein engineering, there is growing interest in site-specifically labeling native (nonengineered) antibodies without chemical or enzymatic treatments. In this review, we highlight recent strategies for producing site-specific native antibody conjugates and provide a comprehensive summary of the merits and disadvantages of these strategies.


Subject(s)
Genetic Code , Immunoconjugates , Protein Engineering
13.
Chem Soc Rev ; 50(18): 10403-10421, 2021 Sep 20.
Article in English | MEDLINE | ID: mdl-34320043

ABSTRACT

There has been a significant push in recent years to deploy fundamental knowledge and methods of photochemistry toward biological ends. Photoreactive groups have enabled chemists to activate biological function using the concept of photocaging. By granting spatiotemporal control over protein activation, these photocaging methods are fundamental in understanding biological processes. Peptides and proteins are an important group of photocaging targets that present conceptual and technical challenges, requiring precise chemoselectivity in complex polyfunctional environments. This review focuses on recent advances in photocaging techniques and methodologies, as well as their use in living systems. Photocaging methods include genetic and chemical approaches that require a deep understanding of structure-function relationships based on subtle changes in primary structure. Successful implementation of these ideas can shed light on important spatiotemporal aspects of living systems.


Subject(s)
Biological Phenomena , Proteins , Peptides , Photochemistry
14.
Org Lett ; 23(14): 5334-5338, 2021 07 16.
Article in English | MEDLINE | ID: mdl-34212723

ABSTRACT

Boronic acids can play diverse roles when applied in biological environments, and employing boronic acid structures in tandem could provide new tools for multifunctional probes. This Letter describes a pair of boronic acid functional groups, 2-nitro-arylboronic acid (NAB) and (E)-alkenylboronic acid (EAB), that enable sequential cross-coupling through stepwise nickel- and copper-catalyzed processes. The selective coupling of NAB groups enables the preparation of stapled peptides, protein-protein conjugates, and other bioconjugates.


Subject(s)
Boronic Acids/chemistry , Nitro Compounds/chemistry , Catalysis , Copper/chemistry , Molecular Structure , Nickel/chemistry , Peptides/chemistry , Proteins/chemistry
15.
Org Biomol Chem ; 19(10): 2213-2223, 2021 03 18.
Article in English | MEDLINE | ID: mdl-33349821

ABSTRACT

Photoactivatable protecting groups (PPGs) are useful for a broad range of applications ranging from biology to materials science. In chemical biology, induction of biological processes via photoactivation is a powerful strategy for achieving spatiotemporal control. The importance of cysteine, glutathione, and other bioactive thiols in regulating protein structure/activity and cell redox homeostasis makes modulation of thiol activity particularly useful. One major objective for enhancing the utility of photoactivatable protecting groups (PPGs) in living systems is creating PPGs with longer wavelength absorption maxima and efficient two-photon (TP) absorption. Toward these objectives, we developed a carboxyl- and dimethylamine-functionalized nitrodibenzofuran PPG scaffold (cDMA-NDBF) for thiol photoactivation, which has a bathochromic shift in the one-photon absorption maximum from λmax = 315 nm with the unfunctionalized NDBF scaffold to λmax = 445 nm. While cDMA-NDBF-protected thiols are stable in the presence of UV irradiation, they undergo efficient broad-spectrum TP photolysis at wavelengths as long as 900 nm. To demonstrate the wavelength orthogonality of cDMA-NDBF and NDBF photolysis in a biological setting, caged farnesyltransferase enzyme inhibitors (FTI) were prepared and selectively photoactivated in live cells using 850-900 nm TP light for cDMA-NDBF-FTI and 300 nm UV light for NDBF-FTI. These experiments represent the first demonstration of thiol photoactivation at wavelengths above 800 nm. Consequently, cDMA-NDBF-caged thiols should have broad applicability in a wide range of experiments in chemical biology and materials science.


Subject(s)
Benzofurans/chemistry , Enzyme Inhibitors/pharmacology , Sulfhydryl Compounds/pharmacology , Animals , Benzofurans/chemical synthesis , Benzofurans/radiation effects , Dogs , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/radiation effects , Farnesyltranstransferase/antagonists & inhibitors , Infrared Rays , Madin Darby Canine Kidney Cells , Photolysis/radiation effects , Photons , Sulfhydryl Compounds/chemistry , Sulfhydryl Compounds/radiation effects
16.
Bioconjug Chem ; 31(11): 2494-2498, 2020 11 18.
Article in English | MEDLINE | ID: mdl-33078937

ABSTRACT

Polymer-protein conjugates are hybrid materials with interesting and useful properties. Methods to prepare diverse diblock materials of this sort often struggle to deal with the complexity and size of reagents, and so polymer-protein conjugation represents a stringent testing ground for nontraditional bioconjugation methods, such as metal-catalyzed arylation. This work demonstrates a simple Ni2+-promoted arylation of cysteine residues with end-functionalized polymer-boronic acid reagents, and explores some molecular and physical properties possible in these hybrid structures.


Subject(s)
Boronic Acids/chemistry , Polymers/chemistry , Proteins/chemistry , Catalysis , Dimerization
17.
Org Biomol Chem ; 18(27): 5110-5114, 2020 07 15.
Article in English | MEDLINE | ID: mdl-32519726

ABSTRACT

Light is a uniquely powerful tool for spatiotemporal control of molecular structure, necessitating the development of new photocaging approaches. This communication describes the design, synthesis, and reactivity of two new photoreactive boronic acid reagents for backbone N-H modification and subsequent photocleavage.

18.
Org Biomol Chem ; 18(17): 3288-3296, 2020 05 06.
Article in English | MEDLINE | ID: mdl-32286579

ABSTRACT

Recurrence and drug resistance are major challenges in the treatment of acute myeloid leukemia (AML) that spur efforts to identify new clinical targets and active agents. STAT3 has emerged as a potential target in resistant AML, but inhibiting STAT3 function has proven challenging. This paper describes synthetic studies and biological assays for a naphthalene sulfonamide inhibitor class of molecules that inhibit G-CSF-induced STAT3 phosphorylation in cellulo and induce apoptosis in AML cells. We describe two different approaches to inhibitor design: first, variation of substituents on the naphthalene sulfonamide core allows improvements in anti-STAT activity and creates a more thorough understanding of anti-STAT SAR. Second, a novel approach involving hybrid sulfonamide-rhodium(ii) conjugates tests our ability to use cooperative organic-inorganic binding for drug development, and to use SAR studies to inform metal conjugate design. Both approaches have produced compounds with improved binding potency. In vivo and in cellulo experiments further demonstrate that these approaches can also lead to improved activity in living cells, and that compound 3aa slows disease progression in a xenograft model of AML.


Subject(s)
Antineoplastic Agents/chemistry , Leukemia, Myeloid, Acute/drug therapy , Naphthalenes/chemistry , Protein Kinase Inhibitors/chemistry , STAT3 Transcription Factor/antagonists & inhibitors , Sulfonamides/chemistry , Animals , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Cell Line, Tumor , Drug Screening Assays, Antitumor , Humans , Mice , Models, Molecular , Molecular Targeted Therapy , Neoplasms, Experimental , Oxidation-Reduction , Protein Binding , Protein Kinase Inhibitors/pharmacology , STAT3 Transcription Factor/genetics , Structure-Activity Relationship
19.
Sci Adv ; 6(5): eaax8254, 2020 01.
Article in English | MEDLINE | ID: mdl-32064339

ABSTRACT

Plant-microbe interactions are mediated by signaling compounds that control vital plant functions, such as nodulation, defense, and allelopathy. While interruption of signaling is typically attributed to biological processes, potential abiotic controls remain less studied. Here, we show that higher organic carbon (OC) contents in soils repress flavonoid signals by up to 70%. Furthermore, the magnitude of repression is differentially dependent on the chemical structure of the signaling molecule, the availability of metal ions, and the source of the plant-derived OC. Up to 63% of the signaling repression occurs between dissolved OC and flavonoids rather than through flavonoid sorption to particulate OC. In plant experiments, OC interrupts the signaling between a legume and a nitrogen-fixing microbial symbiont, resulting in a 75% decrease in nodule formation. Our results suggest that soil OC decreases the lifetime of flavonoids underlying plant-microbe interactions.


Subject(s)
Carbon/metabolism , Flavonoids/metabolism , Medicago sativa/metabolism , Soil Microbiology , Metals/metabolism , Minerals/metabolism , Nitrogen/metabolism , Plant Physiological Phenomena , Soil/chemistry
20.
Chem Sci ; 11(38): 10501-10505, 2020 Sep 14.
Article in English | MEDLINE | ID: mdl-34094308

ABSTRACT

Polypeptides present remarkable selectivity challenges for chemical methods. Amino groups are ubiquitous in polypeptide structure, yet few paradigms exist for reactivity and selectivity in arylation of amine groups. This communication describes the utilization of boronic acid reagents bearing certain o-electron withdrawing groups for copper-mediated amine arylation of the N-terminus under mild conditions and primarily aqueous solvent. The method adds to the toolkit of boronic acid reagents for polypeptide modification under mild conditions in water that shows complete selectivity for the N-terminus in the presence of lysine side chains.

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