Improved drug delivery to the brain

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KANAZAWA, Japan, November 8, 2022 /PRNewswire/ — In a study recently published in the journal Nature Biomedical EngineeringKanazawa University researchers are using a method called “roping grafting” to design therapies with improved longevity and brain penetration

Cell growth and repair are stimulated by biomolecules called cytokines and growth factors. Unfortunately, delivering adequate concentrations of these molecules to the brain to treat neurological conditions such as Alzheimer’s disease is difficult because they are either cleared from the blood very quickly or do not enter neural tissue effectively. A research team led by Kunio Matsumoto and Katsuya Sakai at Kanazawa University in collaboration with Junichi Takagi, Osaka University and Hiroaki Suga, the University of Tokyo has now used a technique called “lasso-grafting” to engineer molecules that replicate growth factors with longer retention in the body and brain penetration.

The team synthesized a molecular entity composed of two components: macrocyclic peptides inserted into antibody fragments (called Fc) (Fig. 1a). Macrocyclic peptides are truncated proteins that can be modified to resemble growth factors. Using lasso-grafting, a method previously developed by the researchers, selected peptides were inserted into loops found on Fc. Now, lasso-grafting ensures that the macrocyclic peptides are easily exposed while keeping the structural integrity and function of the peptide and Fc intact. Fc was used for this purpose because it stays in the body long enough and can easily add the functionality of the Fab of choice.

Using this process, a design molecule replicating hepatocyte growth factor (HGF) was first created. HGF binds to a docking protein known as Met on the surface of cells to initiate signaling for cell growth and survival. Thus, aMD4 and aMD5, two macrocyclic peptides that can also bind Met were first identified. They were then grafted into various sites on Fc until optimal insertion sites were found. When exposed to cells, Fc(aMD4) and Fc(aMD5) indeed locked to Met receptors and initiated HGF-like cell signaling (Fig. 1b).

Next, the longevity of Fc(aMD4) compared to Fc and HGF alone was examined. When given to mice, HGF concentrations decreased significantly after one hour while Fc(aMD4) persisted at levels sufficient to activate Met, for up to 200 hours. Cell replication markers were also active in these mice. Fc(aMD4) therefore showed longevity and bioactivity. The last step was to determine the penetration into the brain of these designer molecules. For this purpose, aMD4 was inserted into an anti-transferrin receptor (TfR) antibody Fc that accumulates in mouse brain after peripheral delivery (Fig. 1c). Indeed, TfR(aMD4) showed high accumulation and retention in brain tissues of mice compared to Fc(aMD4) alone.

This study describes a new strategy for inducing the effects of growth factors and cytokines with better retention in brain tissue. Moreover, based on the selected macrocyclic peptides and antibodies, this technique can be applied to mimic several growth factors. “Thus, lasso grafting enables the design of therapeutic proteins with the desired physicochemical stability and controllable pharmacokinetics, as well as the rapid engineering of antibodies for multiple functionalities,” the researchers suggest.

Background

Macrocyclic Peptides: Macrocyclic peptides are short fragments of proteins. Their cyclic structure facilitates strong binding to proteins of interest. Macrocyclic peptides are being investigated in drug development because advanced techniques such as in vitro displays now make it easy to discover peptides that can bind to a desired target. The lasso-grafting method developed by the researchers here also allows easy incorporation of macrocyclic peptides into protein scaffolds that can generate multifunctional proteins.

Reference

Katsuya Sakai, Nozomi Sugano-Nakamura, Emiko MiharaRojas-Chaverra NM, Sayako Watanabe, Hiroki Sato, Ryu Imamura, Dominic Chih-Cheng Voon, Itsuki Sakai, Chihiro Yamasaki, Chise Tateno, Mikihiro Shibata, Hiroaki Suga, Junichi Takagi, Kunio Matsumoto. Design receptor agonists with improved pharmacokinetics by grafting macrocyclic peptides into crystallizable regions of fragments. biomedical engineering from nature, 2022.

DOI: 10.1038/s41551-022-00955-6

https://www.nature.com/articles/s41551-022-00955-6

Founded by: Japan Society for the Promotion of Science, Japan Agency for Medical Research and Development, World Premier International Research Center Initiative (WPI), MEXT, Japan

Associated image

https://nanolsi.kanazawa-u.ac.jp/wp-content/uploads/2022/08/Figure_1.png

Fig. 1. Lasso grafting to engineer molecules that mimic growth factors with longer brain retention and penetration. (a) A pharmacophore sequence of the Met receptor-binding macrocyclic peptide (aMD4; shown in red) was inserted into the loops (colored balls) of the human IgG1 Fc protein. (b) Fc lasso transplantation yields Met agonists with prolonged half-life in the body. (vs) Lasso Fc grafting of an anti-TfR antibody yields Met agonists with penetrance of the blood-brain barrier (BBB).

Contact
Hiroe Yoneda
Deputy Director of Public Affairs
WPI Nano Life Sciences Institute (WPI-NanoLSI)
Kanazawa University
Kakuma-machi, Kanazawa 920-1192, Japan
Email: [email protected]
Tel: +81 (76) 234-4550

About the Nano Life Science Institute (WPI-NanoLSI)

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The Nano Life Science Institute (NanoLSI) at Kanazawa University is a research center established in 2017 under the World Premier International Research Center Initiative of the Ministry of Education, Culture, Sports, Science and Technology. The objective of this initiative is to create world-class research centres. NanoLSI combines the most advanced knowledge of biological probe microscopy to establish “nano-endoscopic techniques” to directly image, analyze and manipulate biomolecules to better understand the mechanisms governing life phenomena such as diseases.

About Kanazawa University

http://www.kanazawa-u.ac.jp/e/

As the leading comprehensive university in the sea of Japan coast, Kanazawa University has contributed greatly to higher education and academic research in Japan since its founding in 1949. The University has three colleges and 17 schools offering courses in subjects including medicine, computer engineering, and humanities.

The University is located on the sea coast of Japan in Kanazawa – a city rich in history and culture. The city of Kanazawa has had a highly respected intellectual profile since the time of the feud (1598-1867). The University of Kanazawa is divided into two main campuses: Kakuma and Takaramachi for its approximately 10,200 students, including 600 foreigners.

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