- Functional virus-based polymer-protein nanoparticles by atom transfer radical polymerization
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Viruses and virus-like particles (VLPs) are useful tools in biomedical research. Their defined structural attributes make them attractive platforms for engineered interactions over large molecular surface areas. In this report, we describe the use of VLPs as multivalent macroinitiators for atom transfer radical polymerization. The introduction of chemically reactive monomers during polymerization provides a robust platform for post-synthetic modification via the copper-catalyzed azide-alkyne cycloaddition reaction. These results provide the basis to construct nanoparticle delivery vehicles and imaging agents using protein-polymer conjugates.
- Pokorski, Jonathan K.,Breitenkamp, Kurt,Liepold, Lars O.,Qazi, Shefah,Finn
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Read Online
- Enzymatic Fluorination of Biotin and Tetrazine Conjugates for Pretargeting Approaches to Positron Emission Tomography Imaging
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The use of radiolabelled antibodies and antibody-derived recombinant constructs has shown promise for both imaging and therapeutic use. In this context, the biotin–avidin/streptavidin pairing, along with the inverse-electron-demand Diels–Alder (iEDDA) rea
- Lowe, Phillip T.,Dall'Angelo, Sergio,Devine, Andrew,Zanda, Matteo,O'Hagan, David
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Read Online
- Facial Synthesis and Bioevaluation of Well‐Defined OEGylated Betulinic Acid‐Cyclodextrin Conjugates for Inhibition of Influenza Infection
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Betulinic acid (BA) and its derivatives exhibit a variety of biological activities, especially their anti‐HIV‐1 activity, but generally have only modest inhibitory potency against influenza virus. The entry of influenza virus into host cells can be competitively inhibited by multivalent derivatives targeting hemagglutinin. In this study, a series of hexa‐, hepta‐ and octavalent BA derivatives based on α-, β-and γ-cyclodextrin scaffolds, respectively, with varying lengths of flexible oligo(ethylene glycol) linkers was designed and synthesized using a microwave‐assisted copper‐catalyzed 1,3‐di-polar cycloaddition reaction. The generated BA‐cyclodextrin conjugates were tested for their in vitro activity against influenza A/WSN/33 (H1N1) virus and cytotoxicity. Among the tested com-pounds, 58, 80 and 82 showed slight cytotoxicity to Madin‐Darby canine kidney cells with viabilities ranging from 64 to 68% at a high concentration of 100 μM. Four conjugates 51 and 69–71 showed significant inhibitory effects on influenza infection with half maximal inhibitory concentration val-ues of 5.20, 9.82, 7.48 and 7.59 μM, respectively. The structure‐activity relationships of multivalent BA‐cyclodextrin conjugates were discussed, highlighting that multivalent BA derivatives may be potential antiviral agents against influenza infection.
- Chen, Yingying,Gao, Qianqian,Liang, Shuobin,Ma, Xinyuan,Tretyakova, Elena V.,Wang, Xinchen,Xiao, Sulong,Zhang, Yongmin,Zhou, Demin
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- COMPOSITIONS AND METHODS RELATED TO MOLECULAR CONJUGATION
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The invention relates to activated Michael acceptor (AMA) compounds that can undergo conjugation with biomolecules containing Michael donor moieties, thereby providing plasma-stable antibody-drug conjugates (ADCs). Pharmaceutical compositions of the ADCs are disclosed as well. Also provided herein are a number of applications (e.g., therapeutic applications) in which the compositions are useful.
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Page/Page column 48; 49
(2021/06/11)
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- ANTIBODY COMPOUNDS WITH REACTIVE ARGININE AND RELATED ANTIBODY DRUG CONJUGATES
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The present invention provides antibody compounds that contain a substitution of arginine for the reactive lysine residue (Lys99) in the hydrophobic cleft (38C2_Arg). The invention also provides antibody drug conjugate compounds (ADCs) that contain cargo
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Paragraph 00151-00152; 00155
(2020/05/19)
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- A MedChem toolbox for cereblon-directed PROTACs
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A modular chemistry toolbox was developed for cereblon-directed PROTACs. A variety of linkers was attached to a CRBN ligand via the 4-amino position of pomalidomide. We used linkers of different constitution to modulate physicochemical properties. We equipped one terminus of the linker with a set of functional groups, e.g. protected amines, protected carboxylic acids, alkynes, chloroalkanes, and protected alcohols, all of which are considered to be attractive for PROTAC design. We also highlight different opportunities for the expansion of the medicinal chemists' PROTAC toolbox towards heterobifunctional molecules, e.g. with biotin, fluorescent, hydrophobic and peptide tags.
- Steinebach, Christian,Sosi?, Izidor,Lindner, Stefanie,Bricelj, Ale?a,Kohl, Franziska,Ng, Yuen Lam Dora,Monschke, Marius,Wagner, Karl G.,Kr?nke, Jan,Gütschow, Michael
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p. 1037 - 1041
(2019/06/27)
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- ANTIBODY-DRUG CONJUGATES
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An antibody-drug conjugate (ADC) has a structure represented by Formula (I): [in-line-formulae][D2-L2-Cn2?yG2-Ab-Sg1?G1-L1-D1]x?? Formula (I)[/in-line-formulae]or a pharmaceutically acceptable salt thereof, wherein Ab is an antibody without glycans (i.e., the protein portion of an antibody);G1 and G2 are glycan moieties, which may be the same or different;Cn1 and Cn2 are conjugation moieties, which may be the same or different;L1 and L2 are linker moieties, which may be the same or different;D1 and D2 are drug units which may be the same or different; andx and y are independently an integer from 0 to 8, provided that x+y≠0.
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Paragraph 0140; 0142
(2018/05/26)
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- In vivo programming of endogenous antibodies via oral administration of adaptor ligands
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Vaccination is a reliable method of prophylaxis and a crucial measure for public health. However, the majority of vaccines cannot be administered orally due to their degradation in the harsh gut environment or inability to cross the GI tract. In this stud
- Nagano, Masanobu,Carrillo, Nancy,Otsubo, Nobumasa,Hakamata, Wataru,Ban, Hitoshi,Fuller, Roberta P.,Bashiruddin, Nasir K.,Barbas, Carlos F.
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p. 5952 - 5961
(2017/10/10)
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- Enzymatic transhalogenation of dendritic RGD peptide constructs with the fluorinase
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The substrate scope of fluorinase enzyme mediated transhalogenation reactions is extended. Substrate tolerance allows a peptide cargo to be tethered to a 5′-chloro-5′-deoxynucleoside substrate for transhalogenation by the enzyme to a 5′-fluoro-5′-deoxynuc
- Thompson, Stephen,Fleming, Ian N.,O'Hagan, David
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supporting information
p. 3120 - 3129
(2016/03/19)
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- HIGH MOLECULAR WEIGHT ZWITTERION-CONTAINING POLYMERS
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The present invention provides multi-armed high MW polymers containing hydrophilic groups and one or more functional agents, and methods of preparing such polymers.
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Paragraph 0428; 0429
(2014/02/16)
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- A modular approach to triazole-containing chemical inducers of dimerisation for yeast three-hybrid screening
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The yeast three-hybrid (Y3H) approach shows considerable promise for the unbiased identification of novel small molecule-protein interactions. In recent years, it has been successfully used to link a number of bioactive molecules to novel protein binding partners. However despite its potential importance as a protein target identification method, the Y3H technique has not yet been widely adopted, in part due to the challenges associated with the synthesis of the complex chemical inducers of dimerisation (CIDs). The development of a modular approach using potentially "off the shelf" synthetic components was achieved and allowed the synthesis of a family of four triazole-containing CIDs, MTX-Cmpd2.2-2.5. These CIDs were then compared using the Y3H approach with three of them giving a strong positive interaction with a known target of compound 2, TgCDPK1. These results showed that the modular nature of our synthetic strategy may help to overcome the challenges currently encountered with CID synthesis and should contribute to the Y3H approach reaching its full potential as an unbiased target identification strategy.
- Tran, Fanny,Odell, Anahi V.,Ward, Gary E.,Westwood, Nicholas J.
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supporting information
p. 11639 - 11657
(2013/10/22)
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- Efficient synthesis of diverse heterobifunctionalized clickable oligo(ethylene glycol) linkers: Potential applications in bioconjugation and targeted drug delivery
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Herein we describe the sequential synthesis of a variety of azide-alkyne click chemistry-compatible heterobifunctional oligo(ethylene glycol) (OEG) linkers for bioconjugation chemistry applications. Synthesis of these bioorthogonal linkers was accomplished through desymmetrization of OEGs by conversion of one of the hydroxyl groups to either an alkyne or azido functionality. The remaining distal hydroxyl group on the OEGs was activated by either a 4-nitrophenyl carbonate or a mesylate (-OMs) group. The -OMs functional group served as a useful precursor to form a variety of heterobifunctionalized OEG linkers containing different highly reactive end groups, e.g., iodo, -NH2, -SH and maleimido, that were orthogonal to the alkyne or azido functional group. Also, the alkyne- and azide-terminated OEGs are useful for generating larger discrete poly(ethylene glycol) (PEG) linkers (e.g., PEG 16 and PEG24) by employing a Cu(i)-catalyzed 1,3-dipolar cycloaddition click reaction. The utility of these clickable heterobifunctional OEGs in bioconjugation chemistry was demonstrated by attachment of the integrin (αvβ3) receptor targeting peptide, cyclo-(Arg-Gly-Asp-d-Phe-Lys) (cRGfKD) and to the fluorescent probe sulfo-rhodamine B. The synthetic methodology presented herein is suitable for the large scale production of several novel heterobifunctionalized OEGs from readily available and inexpensive starting materials.
- Goswami, Lalit N.,Houston, Zachary H.,Sarma, Saurav J.,Jalisatgi, Satish S.,Hawthorne, M. Frederick
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p. 1116 - 1126
(2013/03/28)
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- 1,2,3-Triazoles as amide bond mimics: Triazole scan yields protease-resistant peptidomimetics for tumor targeting
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The triazole makes the difference: Replacement of amide bonds in the backbone of peptides by 1,4-disubstituted 1,2,3-triazole isosteres affords peptidomimetics with retained receptor affinity and cell-internalization properties, enhanced proteolytic stability, and improved tumor-targeting capabilities. Copyright
- Valverde, Ibai E.,Bauman, Andreas,Kluba, Christiane A.,Vomstein, Sandra,Walter, Martin A.,Mindt, Thomas L.
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p. 8957 - 8960
(2013/09/02)
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- BIFUNCTIONAL MOLECULES WITH ANTIBODY-RECRUITING AND ENTRY INHIBITORY ACTIVITY AGAINST THE HUMAN IMMUNODEFICIENCY VIRUS
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The present invention is directed to new bifunctional compounds and methods for treating HIV infections. The bifunctional small molecules, generally referred to as ARM-H′ function through orthogonal pathways, by inhibiting the gp120-CD4 interaction, and b
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Page/Page column 31
(2012/11/07)
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- An antibody-recruiting small molecule that targets HIV gp120
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(Chemical Equation Presented) HIV/AIDS is a global pandemic for which new treatment strategies are desperately needed. We have designed a novel small molecule, designated as ARM-H, that has the potential to interfere with HIV survival through two mechanis
- Parker, Christopher G.,Domaoal, Robert A.,Anderson, Karen S.,Spiegel, David A.
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supporting information; experimental part
p. 16392 - 16394
(2010/02/16)
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- Chemical control over immune recognition: A class of antibody-recruiting small molecules that target prostate cancer
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(Figure Presented) Prostate cancer is the second leading cause of cancer-related death among the American male population, and society is in dire need of new approaches to treat this disease. Here we report the design, synthesis, and biological evaluation
- Murelli, Ryan P.,Zhang, Andrew X.,Michel, Julien,Jorgensen, William L.,Spiegel, David A.
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supporting information; experimental part
p. 17090 - 17092
(2010/03/25)
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- Lacosamide isothiocyanate-based agents: Novel agents to target and identify lacosamide receptors
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(R)-Lacosamide ((R)-2, (R)-N-benzyl 2-acetamido-3-methoxypropionamide) has recently gained regulatory approval for the treatment of partial-onset seizures in adults.Whole animal pharmacological studies have documented that (R)-2 function is unique. A robust strategy is advanced for the discovery of interacting proteins associated with function and toxicity of (R)-2 through the use of (R)-2 analogues, 3, which contain "affinity bait (AB)" and "chemical reporter (CR)" functional groups. In 3, covalent modification of the interacting proteins proceeds at the AB moiety, and detection or isolation of the selectively captured protein occurs through the bioorthogonal CR group upon reaction with an appropriate probe. We report the synthesis, pharmacological evaluation, and interrogation of the mouse soluble brain proteome using 3 where the AB group is an isothiocyanate moiety. One compound, (R)-N-(4-isothiocyanato)benzyl 2-acetamido-3-(prop-2-ynyloxy) propionamide ((R)-9), exhibited excellent seizure protection in mice, and like (R)-2, anticonvulsant activity principally resided in the (R)-stereoisomer. Several proteins were preferentially labeled by (R)-9 compared with (S)-9, including collapsin response mediator protein 2. 2009 American Chemical Society.
- Ki, Duk Park,Morieux, Pierre,Salomé, Christophe,Cotten, Steven W.,Reamtong, Onrapak,Eyers, Claire,Gaskell, Simon J.,Stables, James P.,Liu, Rihe,Kohn, Harold
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supporting information; experimental part
p. 6897 - 6911
(2010/04/24)
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- One-step bioengineering of magnetic nanoparticles via a surface diazo transfer/azide-alkyne click reaction sequence
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We have developed an efficient conversion of amino iron oxides to carbohydrate and protein derived nanoparticles with highly conserved bioactivity through a combination of diazo transfer and azide-alkyne click technology. The Royal Society of Chemistry.
- Polito, Laura,Monti, Diego,Caneva, Enrico,Delnevo, Eleonora,Russo, Giovanni,Prosperi, Davide
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p. 621 - 623
(2008/09/21)
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