Effects of C7 substitutions in a high affinity microtubule-binding taxane on antitumor activity and drug transport

2011 ◽  
Vol 21 (16) ◽  
pp. 4852-4856 ◽  
Author(s):  
Xi Xiao ◽  
Ju Wu ◽  
Chiara Trigili ◽  
Hui Chen ◽  
Joseph W.K. Chu ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Drug Transport ◽  
Microtubule Binding ◽  
High Affinity

scholarly journals Pre-clinical characterisation of E2814, a high-affinity antibody targeting the microtubule-binding repeat domain of tau for passive immunotherapy in Alzheimer’s disease

2020 ◽  
Vol 8 (1) ◽  
Author(s):  
Malcolm Roberts ◽  
Ioanna Sevastou ◽  
Yoichi Imaizumi ◽  
Kavita Mistry ◽  
Sonia Talma ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
In Vivo Model ◽  
Sequence Motif ◽  
Antibody Treatment ◽  
Microtubule Binding ◽  
High Affinity ◽  
The Brain

AbstractTau deposition in the brain is a pathological hallmark of many neurodegenerative disorders, including Alzheimer’s disease (AD). During the course of these tauopathies, tau spreads throughout the brain via synaptically-connected pathways. Such propagation of pathology is thought to be mediated by tau species (“seeds”) containing the microtubule binding region (MTBR) composed of either three repeat (3R) or four repeat (4R) isoforms. The tau MTBR also forms the core of the neuropathological filaments identified in AD brain and other tauopathies. Multiple approaches are being taken to limit tau pathology, including immunotherapy with anti-tau antibodies. Given its key structural role within fibrils, specifically targetting the MTBR with a therapeutic antibody to inhibit tau seeding and aggregation may be a promising strategy to provide disease-modifying treatment for AD and other tauopathies. Therefore, a monoclonal antibody generating campaign was initiated with focus on the MTBR. Herein we describe the pre-clinical generation and characterisation of E2814, a humanised, high affinity, IgG1 antibody recognising the tau MTBR. E2814 and its murine precursor, 7G6, as revealed by epitope mapping, are antibodies bi-epitopic for 4R and mono-epitopic for 3R tau isoforms because they bind to sequence motif HVPGG. Functionally, both antibodies inhibited tau aggregation in vitro. They also immunodepleted a variety of MTBR-containing tau protein species. In an in vivo model of tau seeding and transmission, attenuation of deposition of sarkosyl-insoluble tau in brain could also be observed in response to antibody treatment. In AD brain, E2814 bound different types of tau filaments as shown by immunogold labelling and recognised pathological tau structures by immunohistochemical staining. Tau fragments containing HVPGG epitopes were also found to be elevated in AD brain compared to PSP or control. Taken together, the data reported here have led to E2814 being proposed for clinical development.

scholarly journals Cryo-EM of dynein microtubule-binding domains shows how an axonemal dynein distorts the microtubule

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Samuel E Lacey ◽  
Shaoda He ◽  
Sjors HW Scheres ◽  
Andrew P Carter
Keyword(s):  
Conformational Changes ◽  
Coiled Coil ◽  
Cytoplasmic Dynein ◽  
Cross Sectional ◽  
Microtubule Binding ◽  
High Affinity ◽  
Binding Domains ◽  
Microtubule Binding Domain ◽  
Axonemal Dynein ◽  
Cilia And Flagella

Dyneins are motor proteins responsible for transport in the cytoplasm and the beating of axonemes in cilia and flagella. They bind and release microtubules via a compact microtubule-binding domain (MTBD) at the end of a coiled-coil stalk. We address how cytoplasmic and axonemal dynein MTBDs bind microtubules at near atomic resolution. We decorated microtubules with MTBDs of cytoplasmic dynein-1 and axonemal dynein DNAH7 and determined their cryo-EM structures using helical Relion. The majority of the MTBD is rigid upon binding, with the transition to the high-affinity state controlled by the movement of a single helix at the MTBD interface. DNAH7 contains an 18-residue insertion, found in many axonemal dyneins, that contacts the adjacent protofilament. Unexpectedly, we observe that DNAH7, but not dynein-1, induces large distortions in the microtubule cross-sectional curvature. This raises the possibility that dynein coordination in axonemes is mediated via conformational changes in the microtubule.

scholarly journals Synthesis and Discovery of High Affinity Folate Receptor-Specific Glycinamide Ribonucleotide Formyltransferase Inhibitors with Antitumor Activity

2008 ◽  
Vol 51 (16) ◽  
pp. 5052-5063 ◽  
Author(s):  
Yijun Deng ◽  
Yiqiang Wang ◽  
Christina Cherian ◽  
Zhanjun Hou ◽  
Steven A. Buck ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Folate Receptor ◽  
Glycinamide Ribonucleotide Formyltransferase ◽  
High Affinity

scholarly journals Development of a new high‐affinity human antibody with antitumor activity against solid and blood malignancies

2018 ◽  
Vol 32 (9) ◽  
pp. 5063-5077 ◽  
Author(s):  
Mouldy Sioud ◽  
Phuong Westby ◽  
Vlada Vasovic ◽  
Yngvar Fløisand ◽  
Qian Peng
Keyword(s):  
Antitumor Activity ◽  
Human Antibody ◽  
High Affinity

scholarly journals Myosin-Va Binds to and Mechanochemically Couples Microtubules to Actin Filaments

2004 ◽  
Vol 15 (1) ◽  
pp. 151-161 ◽  
Author(s):  
Tracy T. Cao ◽  
Wakam Chang ◽  
Sarah E. Masters ◽  
Mark S. Mooseker
Keyword(s):  
Actin Filaments ◽  
Binding Protein ◽  
Tail Domain ◽  
Chick Brain ◽  
Microtubule Binding ◽  
High Affinity ◽  
Fluorescence And Electron Microscopy ◽  
Free Microtubules ◽  
Myosin Va ◽  
Cross Links

Myosin-Va was identified as a microtubule binding protein by cosedimentation analysis in the presence of microtubules. Native myosin-Va purified from chick brain, as well as the expressed globular tail domain of this myosin, but not head domain bound to microtubule-associated protein-free microtubules. Binding of myosin-Va to microtubules was saturable and of moderately high affinity (∼1:24 Myosin-Va:tubulin; Kd = 70 nM). Myosin-Va may bind to microtubules via its tail domain because microtubule-bound myosin-Va retained the ability to bind actin filaments resulting in the formation of cross-linked gels of microtubules and actin, as assessed by fluorescence and electron microscopy. In low Ca2+, ATP addition induced dissolution of these gels, but not release of myosin-Va from MTs. However, in 10 μM Ca2+, ATP addition resulted in the contraction of the gels into aster-like arrays. These results demonstrate that myosin-Va is a microtubule binding protein that cross-links and mechanochemically couples microtubules to actin filaments.

scholarly journals Cryo-EM of dynein microtubule-binding domains shows how an axonemal dynein distorts the microtubule

2019 ◽  
Author(s):  
Samuel E. Lacey ◽  
Shaoda He ◽  
Sjors H. W. Scheres ◽  
Andrew P. Carter
Keyword(s):  
Conformational Changes ◽  
Coiled Coil ◽  
Cytoplasmic Dynein ◽  
Cross Sectional ◽  
Microtubule Binding ◽  
High Affinity ◽  
Binding Domains ◽  
Microtubule Binding Domain ◽  
Axonemal Dynein ◽  
Cilia And Flagella

AbstractDyneins are motor proteins responsible for transport in the cytoplasm and the beating of the axoneme in cilia and flagella. They bind and release microtubules via a compact microtubule-binding domain (MTBD) at the end of a long coiled-coil stalk. Here we address how cytoplasmic and axonemal dynein MTBDs bind microtubules at near atomic resolution. We decorated microtubules with MTBDs of cytoplasmic dynein-1 and axonemal dynein DNAH7 and determined their cryo-EM structures using the stand-alone Relion package. We show the majority of the MTBD is remarkably rigid upon binding, with the transition to the high affinity state controlled by the movement of a single helix at the MTBD interface. In addition DNAH7 contains an 18-residue insertion, found in many axonemal dyneins, that reaches over and contacts the adjacent protofilament. Unexpectedly we observe that DNAH7, but not dynein-1, induces large distortions in the microtubule cross-sectional curvature. This raises the possibility that dynein coordination in axonemes is mediated via conformational changes in the microtubule.

Rationally Designed High-Affinity 2-Amino-6-halopurine Heat Shock Protein 90 Inhibitors That Exhibit Potent Antitumor Activity

2007 ◽  
Vol 50 (12) ◽  
pp. 2767-2778 ◽  
Author(s):  
Srinivas R. Kasibhatla ◽  
Kevin Hong ◽  
Marco A. Biamonte ◽  
David J. Busch ◽  
Patricia L. Karjian ◽  
...  
Keyword(s):  
Heat Shock ◽  
Antitumor Activity ◽  
Heat Shock Protein ◽  
Heat Shock Protein 90 ◽  
High Affinity
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