Un-natural mRNAs modified with sulfur atoms boost efficient protein
synthesis
Towards the development of mRNA therapeutics and new methods of protein production

Date:
July 16, 2020
Source:
Japan Science and Technology Agency
Summary:
A group of scientists has succeeded in the development of modified
messenger RNAs (mRNAs) that contain sulfur atoms in the place
of oxygen atoms of phosphate moieties of natural mRNAs. They
discovered that modified mRNAs accelerated the initiation step
of the translation reactions and improved efficiency of protein
synthesis by at least 20 times compared with that using natural-form
mRNAs.



FULL STORY ========================================================================== Since mRNAs play a key role in protein synthesis in vivo, the use of mRNAs
as medicines and for in vitro protein synthesis has been desired. In particular, mRNA therapeutics hold the potential for application to
vaccine therapy(1) against coronaviruses and are being developed. However,
the efficiency of protein production with mRNAs in the natural form
is not sufficient enough for certain purposes, including application
to mRNA therapeutics. Therefore, mRNA molecules allowing for efficient
protein production have been required to be developed.


==========================================================================
A ribosome(2) repeats the following three steps to synthesize a
protein in vivo using an mRNA as a template (translation reaction):
1) Initiation step: A ribosome binds to an mRNA to form a translation initiation complex; 2) Elongation step: The ribosome moves on the mRNA and links amino acids to synthesize a protein; and 3) Termination step: The
protein synthesis process concludes, and the ribosome is liberated. In the translation reaction cycle, the initiation step takes the longest time.

Collaborative research by a group of Nagoya University consisting
of Professor Hiroshi Abe, Research Assistant Professor Naoko Abe, and
graduate student Daisuke Kawaguchi with Yoshihiro Shimizu, a team leader
at RIKEN, has succeeded in the development of modified messenger RNAs
(mRNAs). The modified mRNA contains sulfur atoms in the place of oxygen
atoms of phosphate moieties of natural mRNAs. It is capable of supporting protein synthesis at increased efficiency. They discovered that modified
mRNAs accelerated the initiation step of the translation reactions and
improved efficiency of protein synthesis by at least 20 times compared
with that using natural-form mRNAs." This method is expected to be used
for large-scale synthesis of proteins as raw materials for the production
of biomaterials. Moreover, the application of the results obtained
in this study to eukaryotic translation systems enables the efficient production of mRNA therapeutics for protein replacement therapy(3) to contribute to medical treatments. Furthermore, there are virtually no
previous reports on the molecular design of highly functional mRNAs;
therefore, the successful design achieved in this study can guide a
future direction of the molecular design of modified mRNAs.

This study was supported by the Strategic Basic Research Program CREST
of the Japan Science and Technology Agency (JST).

(1) Vaccine therapy A method of administering a protein antigen to
individuals to elicit antibodies that can reduce the susceptibility to infectious diseases. In the case of an mRNA vaccine, an mRNA for in vivo expression of an antigen protein is administered, and then antibodies
are produced against the expressed antigen protein.

(2) Ribosome Multicomponent machinery providing a place where sequence information of an mRNA is read, and a protein is synthesized based on
the sequence information while migrating on the mRNA. A ribosome is
composed of ribosomal proteins and ribosomal RNAs.

(3) Protein replacement therapy A treatment method that aims at
improvement by supplementing protein from the outside when the deficiency
of proteins (enzymes, etc.) is a cause of an illness.


========================================================================== Story Source: Materials provided by
Japan_Science_and_Technology_Agency. Note: Content may be edited for
style and length.


========================================================================== Journal Reference:
1. Hiroshi Abe, Daisuke Kawaguchi, Ayumi Kodama, Naoko Abe, Kei
Takebuchi,
Fumitaka Hashiya, Fumiaki Tomoike, Kousuke Nakamoto, Yasuaki
Kimura, Yoshihiro Shimizu. Phosphorothioate Modification of mRNA
Accelerates Rate of Translation Initiation Providing More Efficient
Protein Synthesis.

Angewandte Chemie International Edition, 2020; DOI: 10.1002/
anie.202007111 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/07/200716101534.htm

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