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47 results on '"Dong, Xianchi"'

3. De novo design of highly selective miniprotein inhibitors of integrins αvβ6 and αvβ8

Author

Roy, Anindya, Shi, Lei, Chang, Ashley, Dong, Xianchi, Fernandez, Andres, Kraft, John C., Li, Jing, Le, Viet Q., Winegar, Rebecca Viazzo, Cherf, Gerald Maxwell, Slocum, Dean, Poulson, P. Daniel, Casper, Garrett E., Vallecillo-Zúniga, Mary L., Valdoz, Jonard Corpuz, Miranda, Marcos C., Bai, Hua, Kipnis, Yakov, Olshefsky, Audrey, Priya, Tanu, Carter, Lauren, Ravichandran, Rashmi, Chow, Cameron M., Johnson, Max R., Cheng, Suna, Smith, McKaela, Overed-Sayer, Catherine, Finch, Donna K., Lowe, David, Bera, Asim K., Matute-Bello, Gustavo, Birkland, Timothy P., DiMaio, Frank, Raghu, Ganesh, Cochran, Jennifer R., Stewart, Lance J., Campbell, Melody G., Van Ry, Pam M., Springer, Timothy, and Baker, David

Published
2023
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15. The Third dose of CoronVac vaccination induces broad and potent adaptive immune responses that recognize SARS-CoV-2 Delta and Omicron variants

Author

Chen, Yuxin, primary, Chen, Lin, additional, Yin, Shengxia, additional, Tao, Yue, additional, Zhu, Liguo, additional, Tong, Xin, additional, Mao, Minxin, additional, Li, Ming, additional, Wan, Yawen, additional, Ni, Jun, additional, Ji, Xiaoyun, additional, Dong, Xianchi, additional, Li, Jie, additional, Huang, Rui, additional, Shen, Ya, additional, Shen, Han, additional, Bao, Changjun, additional, and Wu, Chao, additional

Published
2022
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26. De novo Design of a Highly Specific Inhibitor of Integrin Αvβ6 for Pulmonary Fibrosis

Author

Roy, Anindya, primary, Shi, Lei, additional, Chang, Ashley, additional, Dong, Xianchi, additional, Li, Jing, additional, Winegar, Rebecca Viazzo, additional, Cherf, Gerald Maxwell, additional, Slocum, Dean, additional, Poulson, P. Daniel, additional, Miranda, Marcos, additional, Bai, Hua, additional, Kipnis, Yakov, additional, Priya, Tanu, additional, Carter, Lauren, additional, Ravichandran, Rashmi, additional, Chow, Cameron M., additional, Overed-Sayer, Catherine, additional, Finch, Donna K., additional, Lowe, David, additional, Stewart, Lance J., additional, Bera, Asim K., additional, Matute-Bello, Gustavo, additional, Birkland, Timothy P., additional, DiMaio, Frank, additional, Raghu, Ganesh, additional, Cochran, Jennifer R., additional, Van Ry, Pam M., additional, Springer, Timothy, additional, and Baker, David, additional

Published
2021
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33. Rules of engagement between αvβ6 integrin and foot-and-mouth disease virus

Author

Kotecha, Abhay, Wang, Quan, Dong, Xianchi, Ilca, Serban L., Ondiviela, Marina, Zihe, Rao, Seago, Julian, Charleston, Bryan, Fry, Elizabeth E., Abrescia, Nicola G. A., Springer, Timothy A., Huiskonen, Juha T., and Stuart, David I.

Subjects
Integrins, Binding Sites, Science, viruses, Amino Acid Motifs, Cryoelectron Microscopy, CHO Cells, biochemical phenomena, metabolism, and nutrition, Virus Replication, Article, Capsid, Cricetulus, Antigens, Neoplasm, Foot-and-Mouth Disease Virus, Polysaccharides, Cricetinae, Animals, Receptors, Virus, Capsid Proteins, Hydrophobic and Hydrophilic Interactions, Oligopeptides, Protein Binding
Abstract

Foot-and-mouth disease virus (FMDV) mediates cell entry by attachment to an integrin receptor, generally αvβ6, via a conserved arginine–glycine–aspartic acid (RGD) motif in the exposed, antigenic, GH loop of capsid protein VP1. Infection can also occur in tissue culture adapted virus in the absence of integrin via acquired basic mutations interacting with heparin sulphate (HS); this virus is attenuated in natural infections. HS interaction has been visualized at a conserved site in two serotypes suggesting a propensity for sulfated-sugar binding. Here we determined the interaction between αvβ6 and two tissue culture adapted FMDV strains by cryo-electron microscopy. In the preferred mode of engagement, the fully open form of the integrin, hitherto unseen at high resolution, attaches to an extended GH loop via interactions with the RGD motif plus downstream hydrophobic residues. In addition, an N-linked sugar of the integrin attaches to the previously identified HS binding site, suggesting a functional role., Foot-and-mouth disease virus binds αvβ6 integrin, via a conserved RGD motif in the flexible, exposed GH loop of capsid protein VP1, for cell entry. Here Kotecha et al. visualize this interaction with the VP1 GH loop extending away from the viral surface, engaging αvβ6 in an open, active state.

Published
2017

39. Specific high affinity interaction of Helicobacter pylori CagL with integrin αVβ6 promotes type IV secretion of CagA into human cells.

Author

Buß, Maren, Tegtmeyer, Nicole, Schnieder, Jennifer, Dong, Xianchi, Li, Jing, Springer, Timothy A., Backert, Steffen, and Niemann, Hartmut H.

Subjects
SECRETION, HELICOBACTER pylori, INTEGRINS, CELL receptors, ONCOGENIC proteins, EPITHELIAL cells, CELLS
Abstract

CagL is an essential pilus surface component of the virulence‐associated type IV secretion system (T4SS) employed by Helicobacter pylori to translocate the oncogenic effector protein CagA into human gastric epithelial cells. CagL contains an RGD motif and integrin α5β1 is widely accepted as its host cell receptor. Here, we show that CagL binds integrin αVβ6 with substantially higher affinity and that this interaction is functionally important. Cell surface expression of αVβ6 on various cell lines correlated perfectly with cell adhesion to immobilized CagL and with binding of soluble CagL to cells. We found no such correlation for α5β1. The purified αVβ6 ectodomain bound CagL with high affinity. This interaction was highly specific, as the affinity of CagL for other RGD‐binding integrins was two to three orders of magnitude weaker. Mutation of either conserved leucine in the CagL RGDLXXL motif, a motif that generally confers specificity for integrin αVβ6 and αVβ8, lowered the affinity of CagL for αVβ6. Stable expression of αVβ6 in αVβ6‐negative but α5β1‐expressing human cells promoted two hallmarks of the functional H. pylori T4SS, namely translocation of CagA into host cells and induction of interleukin‐8 secretion by host cells. These findings suggest that integrin αVβ6, although not essential for T4SS function, represents an important host cell receptor for CagL. [ABSTRACT FROM AUTHOR]

Published
2019
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47. De novo design of highly selective miniprotein inhibitors of integrins αvβ6 and αvβ8.

Author

Roy A, Shi L, Chang A, Dong X, Fernandez A, Kraft JC, Li J, Le VQ, Winegar RV, Cherf GM, Slocum D, Daniel Poulson P, Casper GE, Vallecillo-Zúniga ML, Valdoz JC, Miranda MC, Bai H, Kipnis Y, Olshefsky A, Priya T, Carter L, Ravichandran R, Chow CM, Johnson MR, Cheng S, Smith M, Overed-Sayer C, Finch DK, Lowe D, Bera AK, Matute-Bello G, Birkland TP, DiMaio F, Raghu G, Cochran JR, Stewart LJ, Campbell MG, Van Ry PM, Springer T, and Baker D

Abstract

The RGD (Arg-Gly-Asp)-binding integrins αvβ6 and αvβ8 are clinically validated cancer and fibrosis targets of considerable therapeutic importance. Compounds that can discriminate between the two closely related integrin proteins and other RGD integrins, stabilize specific conformational states, and have sufficient stability enabling tissue restricted administration could have considerable therapeutic utility. Existing small molecules and antibody inhibitors do not have all of these properties, and hence there is a need for new approaches. Here we describe a method for computationally designing hyperstable RGD-containing miniproteins that are highly selective for a single RGD integrin heterodimer and conformational state, and use this strategy to design inhibitors of αvβ6 and αvβ8 with high selectivity. The αvβ6 and αvβ8 inhibitors have picomolar affinities for their targets, and >1000-fold selectivity over other RGD integrins. CryoEM structures are within 0.6-0.7Å root-mean-square deviation (RMSD) to the computational design models; the designed αvβ6 inhibitor and native ligand stabilize the open conformation in contrast to the therapeutic anti-αvβ6 antibody BG00011 that stabilizes the bent-closed conformation and caused on-target toxicity in patients with lung fibrosis, and the αvβ8 inhibitor maintains the constitutively fixed extended-closed αvβ8 conformation. In a mouse model of bleomycin-induced lung fibrosis, the αvβ6 inhibitor potently reduced fibrotic burden and improved overall lung mechanics when delivered via oropharyngeal administration mimicking inhalation, demonstrating the therapeutic potential of de novo designed integrin binding proteins with high selectivity.

Published
2023
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