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In JoVE (1)
- Solid-phase Submonomer Synthesis of Peptoid Polymers and their Self-Assembly into Highly-Ordered Nanosheets
Other Publications (10)
Articles by Michael D. Connolly in JoVE
Solid-phase Submonomer Synthesis of Peptoid Polymers and their Self-Assembly into Highly-Ordered Nanosheets
Helen Tran1, Sarah L. Gael1, Michael D. Connolly1, Ronald N. Zuckermann1
1Molecular Foundry, Lawrence Berkeley National Laboratory
Other articles by Michael D. Connolly on PubMed
Organic Letters. Jul, 2003 | Pubmed ID: 12841749
[reaction: see text] Molecular modeling was used to design mimetics of the HIV-1 matrix protein nuclear localization signal (NLS) in which a scaffold of two resorcinol units joined by a diamide linker presents 3-aminopropyl ethers in place of lysine side chains. Prospective mimetics with linkers of 6, 8, 10, or 12 atoms were synthesized and compared in a competition assay for binding to the nuclear import receptor subunit karyopherin alpha, showing the 10-atom linker to be best and shorter ones ineffective.
Incorporation of Unprotected Heterocyclic Side Chains into Peptoid Oligomers Via Solid-phase Submonomer Synthesis
Journal of the American Chemical Society. Jul, 2003 | Pubmed ID: 12862480
Peptoids (N-substituted glycines) are an important class of biomimetic oligomers that have made a significant impact in the areas of combinatorial drug discovery, gene therapy, drug delivery, and biopolymer folding in recent years. Sequence-specific peptoid oligomers are easily assembled from primary amines by the solid-phase submonomer method. However, most amines that contain heterocyclic nitrogens in the side chain do not incorporate efficiently. We present here a straightforward revision of the submonomer method that allows efficient incorporation of unprotected imidazoles, pyridines, pyrazines, indoles, and quinolines into oligomers as long as 15 monomers in length. This improved method uses chloroacetic acid instead of bromoacetic acid in the acylation step of the monomer addition cycle, and allows for the incorporation of new side chains that should enable the synthesis of peptoids with entirely new properties.
Journal of Leukocyte Biology. Jan, 2008 | Pubmed ID: 17884993
The anti-granulocyte receptor-1 (Gr-1) mAb, RB6-8C5, has been used extensively to deplete neutrophils in mice and to investigate the role of these cells in host defense. RB6-8C5 binds to Ly6G, which is present on neutrophils, and to Ly6C, which is expressed on neutrophils, dendritic cells, and subpopulations of lymphocytes and monocytes. It is thus likely that in vivo administration of RB6-8C5 may deplete not only neutrophils but also other Gr-l+ (Ly6C+) cells. This study describes the use of an Ly6G-specific mAb, 1A8, as an alternative means to deplete neutrophils. In vivo administration of RB6-8C5 reduced blood neutrophils and Gr-1+ monocytes, whereas administration of 1A8 reduced blood neutrophils but not Gr-1+ monocytes. Plasma TNF-alpha in endotoxemia was increased 20-fold by RB6-8C5 pretreatment and fourfold by 1A8 pretreatment. In a wound model, pretreatment with either antibody decreased wound neutrophils and macrophages. TNF-alpha staining in brefeldin-treated wound leukocytes was increased by pretreatment with RB6-8C5, but not 1A8. Neutrophil depletion with 1A8 offers advantages over the use of RB6-8C5, as it preserves non-neutrophil Gr-1+ cells depleted by the anti-Gr-1 antibody. The loss of non-neutrophil Gr-1+ populations in RB6-8C5-treated animals is associated with increased TNF-alpha responses, suggesting these cells may function to suppress TNF-alpha production.
High-throughput Sequencing of Peptoids and Peptide-peptoid Hybrids by Partial Edman Degradation and Mass Spectrometry
Journal of Combinatorial Chemistry. Mar, 2009 | Pubmed ID: 19154119
A method for the rapid sequence determination of peptoids [oligo(N-substituted glycines)] and peptide-peptoid hybrids selected from one-bead-one-compound combinatorial libraries has been developed. In this method, beads carrying unique peptoid (or peptide-peptoid) sequences were subjected to multiple cycles of partial Edman degradation (PED) by treatment with a 1:3 (mol/mol) mixture of phenyl isothiocyanate (PITC) and 9-fluorenylmethyl chloroformate (Fmoc-Cl) to generate a series of N-terminal truncation products for each resin-bound peptoid. After PED, the Fmoc group was removed from the N-terminus and any reacted side chains via piperidine treatment. The resulting mixture of the full-length peptoid and its truncation products was analyzed by matrix-assisted laser desorption ionization (MALDI) mass spectrometry, to reveal the sequence of the full-length peptoid. With a slight modification, the method was also effective in the sequence determination of peptide-peptoid hybrids. This rapid, high-throughput, sensitive, and inexpensive sequencing method should greatly expand the utility of combinatorial peptoid libraries in biomedical and materials research.
Nature Materials. May, 2010 | Pubmed ID: 20383129
The design and synthesis of protein-like polymers is a fundamental challenge in materials science. A biomimetic approach is to explore the impact of monomer sequence on non-natural polymer structure and function. We present the aqueous self-assembly of two peptoid polymers into extremely thin two-dimensional (2D) crystalline sheets directed by periodic amphiphilicity, electrostatic recognition and aromatic interactions. Peptoids are sequence-specific, oligo-N-substituted glycine polymers designed to mimic the structure and functionality of proteins. Mixing a 1:1 ratio of two oppositely charged peptoid 36mers of a specific sequence in aqueous solution results in the formation of giant, free-floating sheets with only 2.7 nm thickness. Direct visualization of aligned individual peptoid chains in the sheet structure was achieved using aberration-corrected transmission electron microscopy. Specific binding of a protein to ligand-functionalized sheets was also demonstrated. The synthetic flexibility and biocompatibility of peptoids provide a flexible and robust platform for integrating functionality into defined 2D nanostructures.
The Journal of Trauma. Oct, 2010 | Pubmed ID: 20938267
Normal vital signs are typically associated with improved outcomes in trauma patients. Whether this association is true for geriatric patients is unclear.
PloS One. 2010 | Pubmed ID: 21209907
Alzheimer's Disease (AD) is the most prevalent form of dementia worldwide, yet the development of therapeutics has been hampered by the absence of suitable biomarkers to diagnose the disease in its early stages prior to the formation of amyloid plaques and the occurrence of irreversible neuronal damage. Since oligomeric AÎ² species have been implicated in the pathophysiology of AD, we reasoned that they may correlate with the onset of disease. As such, we have developed a novel misfolded protein assay for the detection of soluble oligomers composed of AÎ² x-40 and x-42 peptide (hereafter AÎ²40 and AÎ²42) from cerebrospinal fluid (CSF). Preliminary validation of this assay with 36 clinical samples demonstrated the presence of aggregated AÎ²40 in the CSF of AD patients. Together with measurements of total AÎ²42, diagnostic sensitivity and specificity greater than 95% and 90%, respectively, were achieved. Although larger sample populations will be needed to confirm this diagnostic sensitivity, our studies demonstrate a sensitive method of detecting circulating AÎ²40 oligomers from AD CSF and suggest that these oligomers could be a powerful new biomarker for the early detection of AD.
Biochemistry. May, 2011 | Pubmed ID: 21539296
Diseases associated with the misfolding of endogenous proteins, such as Alzheimer's disease and type II diabetes, are becoming increasingly prevalent. The pathophysiology of these diseases is not totally understood, but mounting evidence suggests that the misfolded protein aggregates themselves may be toxic to cells and serve as key mediators of cell death. As such, an assay that can detect aggregates in a sensitive and selective fashion could provide the basis for early detection of disease, before cellular damage occurs. Here we report the evolution of a reagent that can selectively capture diverse misfolded proteins by interacting with a common supramolecular feature of protein aggregates. By coupling this enrichment tool with protein specific immunoassays, diverse misfolded proteins and sub-femtomole amounts of oligomeric aggregates can be detected in complex biological matrices. We anticipate that this near-universal approach for quantitative misfolded protein detection will become a useful research tool for better understanding amyloidogenic protein pathology as well as serve as the basis for early detection of misfolded protein diseases.
The Journal of Trauma. Mar, 2011 | Pubmed ID: 21610339
Ethnic minorities and low income families tend to be in poorer health and have worse outcomes for a spectrum of diseases. Health care provider bias has been reported to potentially affect the distribution of care away from poorer communities, minorities, and patients with a history of substance abuse. Trauma is perceived as a disease of the poor and medically underserved. Minorities are overrepresented in low income populations and are also less likely to possess health insurance leading to a potential overlapping effect. Traumatic brain injury (TBI) is a predominant cause of mortality and long-term morbidity, which imposes a considerable social and financial burden. We therefore sought to determine the independent effect on outcome after TBI from race, insurance status, intoxication on presentation, and median income.
The Development of a Urinary Tract Infection is Associated with Increased Mortality in Trauma Patients
The Journal of Trauma. Dec, 2011 | Pubmed ID: 21768897
In October 2008, Medicare and Medicaid stopped paying for care associated with catheter-related urinary tract infections (UTIs). Although most clinicians agree UTIs are detrimental, there are little data to support this belief.