Tackling difficult therapeutic targets

Synthorx’s unique platform expands the chemical and structural repertoire of protein therapeutics and uncovers new ways to modulate pharmacological properties of biologics, not possible with other technologies. Our ability to incorporate multiple unnatural amino acids at specific sites within a protein allows us to create novel biologics with new chemical functionalities to hit previously undruggable therapeutic targets.

Both internally and in collaboration with pharmaceutical companies, Synthorx is designing and discovering first-in-class protein therapeutics for the treatment of pain, infectious disease, metabolic disease, and cancer. Here are a few of our therapeutic programs.

Spider venom, cysteine knots, and non-opioid pain treatments

Ion channel receptors are genetically validated targets for pain. Potent antagonists of ion channels, called cysteine knots, were first isolated from tarantula venom. These toxin peptides present challenges to chemical synthesis because of their conserved disulfide structures and need for efficient oxidative refolding. The high cost of synthesis and refolding of the toxin peptides and their short half-life in vivo have impeded the therapeutic development of cysteine knots.

The Synthorx platform is being applied to enable scalable cost efficient production of correctly folded cysteine knot proteins as well as site-specifically introduce multiple non-natural amino acids into these toxin peptides to diversify and functionalize the protein as an improved therapeutic. For example, one non-natural amino acid could be used as a bio-conjugation handle to increase serum stability and extend circulating half-life. A second non-natural amino acid at a different site within the same peptide could introduce a structural element that may confer greater potency and/or selectivity.

Antibody drug conjugates and bispecific antibodies to improve cancer treatments

To achieve improved drug efficacy and safety, antibody drug conjugates (ADCs) are designed to preferentially deliver cytotoxic drugs to cells presenting tumor-associated antigens. Bi-specific antibodies that can bind two different antigens simultaneously on the same or distinct proteins and/or cells represent a class of next-generation immunotherapies but are often very difficult to produce. Production of these antibodies can be greatly enabled by incorporation of non-natural amino acids to generate precise control of conjugation sites and stoichiometry. Because of our unique ability to incorporate multiple non-natural amino acids, the Synthorx platform can develop new classes of therapeutic proteins such as multiple warhead-bearing ADCs, bi-specific antibodies, or other multivalent antibody/fragment strategies such as "peptibodies."

New macrocycle antibiotics for an inevitable need

Antibiotic resistance in bacteria is now a major threat to public health and there is a large demand for novel classes of drugs to address this concern. Many naturally occurring macrocycles have been successfully introduced to the clinic. However, their utility is dampened by toxic side effects, such as nephrotoxicity. Using Synthorx’s platform to introduce multiple non-natural amino acids to cyclize (macrocycles) or constrain (staple) peptides and proteins could produce new highly potent as well as selective antibiotics.