New building blocks, with the aim of improved therapeutics

Our novel DNA base pair creates an Expanded Genetic Alphabet

The ‘genetic alphabet’ of DNA constitutes two base pairs (A–T and G–C). In an important discovery in synthetic biology, Synthorx’ scientific founder Dr. Romesberg and his team have crafted new base pairs, including d5SICSTP and dNaMTP (abbreviated X–Y), that can be replicated, maintained, transcribed, and subsequently translated in vivo. The expansion of the genetic alphabet with X and Y allows for the increased storage of information and the incorporation of novel amino acids into new, unique proteins.

Why it matters

Protein therapeutics have delivered tremendous value to patients, but some have limitations which cannot be corrected utilizing the twenty natural amino acids. Many proteins in the cell have dual and often opposing functions owing to interaction with different receptors. Synthorx deploys its novel Expanded Genetic Alphabet platform technology to create proteins that are capable of re-programming receptor interactions to potentially treat disease. Furthermore, the half-life of the protein can also be modulated through site-specific bioconjugation such as incorporation of PEGs. We believe these improved pharmacological properties can make drugs that are more efficacious, safer, and more convenient for patients.

How we accomplish this

A semi-synthetic organism was created that incorporates all the necessary building blocks for scalable synthesis of Synthorin™ proteins

Our proprietary bacterial strain, based on a well-established E. coli protein manufacturing strain, expresses a nucleotide transporter (A) that allows controllable maintenance of X–Y genetic information. Supplementing cultures of this strain with X and Y nucleotides leads to their intracellular accumulation to support replication of the DNA encoding genes containing X–Y (B). Induction of transcription stimulates the cell to express the Synthorin messenger RNA harboring non-canonical codons, and the orthogonal tRNAs that decode them (C). Engineered tRNA synthetase enzymes recognize and specifically charge the Synthorx tRNAs with corresponding novel amino acids (nAA) added to the medium (D). Finally, the cell’s natural translation machinery uses these components to decode X–Y codons, site-specifically introducing nAAs into the desired Synthorin product (E).

Publications

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A semi-synthetic organism that stores and retrieves increased genetic information.
Y. Zhang, J.L. Ptacin, E.C. Fischer, H.R. Aerni, C.E. Caffaro, K. San Jose, A.W. Feldman, C.R. Turner, F.E. Romesberg. Nature (2017) 551:644-647.

A semisynthetic organism engineered for the stable expansion of the genetic alphabet.
Y. Zhang, B.M. Lamb, A.W. Feldman, A.X. Zhou, T. Lavergne, L. Li, F.E. Romesberg. Proc Natl Acad Sci U S A (2017) 114:1317-1322.

The expanded genetic alphabet. (Review)
D.A. Malyshev, F.E. Romesberg. Angew Chem Int Ed Engl (2015) 54:11930-11944.

A semi-synthetic organism with an expanded genetic alphabet
D.A. Malyshev, K. Dhami, T. Lavergne, T. Chen, N. Dai, J.M. Foster, I.R. Corrêa, F.E. Romesberg. Nature (2014) 509:385-388.

Natural-like Replication of an Unnatural Base Pair for the Expansion of the Genetic Alphabet and Biotechnology Applications
L. Li, M. Degardin, T. Lavergne, D. Malyshev, K. Dhami, P. Ordoukhanian, F.E. Romesberg. J Am Chem Soc (2014) 136:826–829.

Efficient and sequence-independent replication of DNA containing a third base pair establishes a functional six-letter genetic alphabet
D.A. Malyshev, K. Dhami, H.T. Quach, T. Laveryne, P. Ordoukhanian, A. Torkamani, F.E. Romesberg. Proc Natl Acad Sci USA (2012) 109:12005-12010.

KlenTaq polymerase replicates unnatural base pairs by inducing a Watson-Crick geometry
K. Betz, D.A. Malyshev, T. Lavergne, W. Welte, K. Diederichs, T.J. Dwyer, P. Ordoukhanian, F.E. Romesberg. A. Marx, Nat Chem Biol (2012) 8:612-614.

Site-specific labeling of DNA and RNA using an efficiently replicated and transcribed class of unnatural base pairs
Y.J. Seo, D.A. Malyshev, T. Lavergne, P. Ordoukhanian, F.E. Romesberg. J Am Chem Soc (2011) 133:19878-19888.

Discovery, characterization, and optimization of an unnatural base pair for expansion of the genetic alphabet
A.M. Leconte, G.T. Hwang, S. Matsuda, P. Capek, Y. Hari, F.E. Romesberg. J Am Chem Soc (2008) 130:2336-2343.

 

DNA research: the path to Synthorins™

1866

Mendel publishes on the heredity of peas and establishes the first laws of genetics.

1944

Avery, McLeod, McCarty define DNA as the carrier of genetic information.

1950

Chargaff establishes rules of base pairing.

1953

Wilkins, Franklin, Watson, and Crick publish the double helix structure of DNA.

1958

Hoagland and Zamecnik discover tRNA.

1962

Rich publishes the first proposal of unnatural base pairs (UBP) and selective pairing of DisoC and DisoG via H-bonding patterns

1964

Nirenberg, Leder, Khorana, and Holley describe triplet nature of the genetic code and genetic code translation.

1973

Cohen and Boyer discover recombinant DNA technology.

1983

Mullis invents the polymerase chain reaction (PCR) technique.

1989

Benner demonstrates in vitro replication and transcription of isoC and isoG.

1992

Benner publishes first in vitro translation using isoC–isoG pair and isoCAG codon.

1997

Kool demonstrates selective dA-dF pairing with reduced complementary H-bonding.

2003

Two scientific teams publish the first human genome sequences.

2006

Hirao publishes first UBP pair that could be PCR amplified with an error rate below 1%.

2009

Romesberg lab publishes first UBP pairs, d5SICS-dNaM (X) and d5SICS-dMMO2 (Y), that can be efficiently PCR amplified and transcribed.

2014

Romesberg lab shows nucleotide transporter allows for replication of XY genetic information in E. coli.

2014

Synthorx founded with technology licensed from the Romesberg Lab at The Scripps Research Institute and secures $6.25M Series A.

2015

Demonstration of in vitro translation of UBPs (X and Y): Synthorx identifies codons and validates in vitro translation.

2016

Synthorx completes $10M Series B and initiates in vivo platform and internal pipeline.

2017

Synthorx initiates scalable recombinant protein production (synthorins) and begins lead candidate selection in two programs.

2017

Romesberg lab publishes on a semi-synthetic organism that stores and retrieves increased genetic information.

2018

Synthorx starts two IND-enabling programs.

2018

Synthorx completes $63M Series C financing.