4WYJ

Adenovirus 3 head domain mutant V239D

4WYJ の概要

• エントリーDOI: 10.2210/pdb4wyj/pdb
• 分子名称: Fiber protein, SULFATE ION (3 entities in total)
• 機能のキーワード: adenovirus head domain, viral protein
• 由来する生物種: Human adenovirus B serotype 3 (HAdV-3)
• 細胞内の位置: Virion : P04501
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 65764.84

構造登録者

Lieber, A.,Zubieta, C.,Fender, P. (登録日: 2014-11-17, 公開日: 2015-07-01, 最終更新日: 2023-09-27)

主引用文献

Richter, M.,Yumul, R.,Wang, H.,Saydaminova, K.,Ho, M.,May, D.,Baldessari, A.,Gough, M.,Drescher, C.,Urban, N.,Roffler, S.,Zubieta, C.,Carter, D.,Fender, P.,Lieber, A.
Preclinical safety and efficacy studies with an affinity-enhanced epithelial junction opener and PEGylated liposomal doxorubicin.
Mol Ther Methods Clin Dev, 2:15005-15005, 2015

PubMed Abstract: A central treatment resistance mechanism in solid tumors is the maintenance of epithelial junctions between malignant cells that prevent drug penetration into the tumor. We have developed a small recombinant protein (JO-1) that triggers the transient opening of intercellular junctions and thus increases the efficacy of monoclonal antibodies and chemotherapeutic drugs without causing toxicity in mouse tumor models. Here, we provide data toward the clinical translation of an affinity-enhanced version of JO-1, which we call JO-4, in combination with PEGylated liposomal doxorubicin (PLD)/Doxil for ovarian cancer therapy. We have presented X-ray crystallography data suggesting a structural basis for the higher affinity of JO-4 to DSG2. We also confirmed JO-4 efficacy in a xenograft model with primary ovarian cancer cells showing that JO-4 can salvage Doxil therapy when given at a dose that was threefold lower than the therapeutic dose. Furthermore, we tested the safety of intravenous JO-4 alone and in combination with Doxil in Macaca fascicularis, an adequate animal model for predicting toxicity in humans. Our studies did not show critical JO-4-related toxicity or an increase of Doxil-related side effects. Our efficacy and safety data will help to support an Investigational new drug-filing for a JO-4/Doxil combination treatment.

PubMed: 26029716
DOI: 10.1038/mtm.2015.5

実験手法

X-RAY DIFFRACTION (2.65 Å)