Many of the “star proteins” of modern medicine—including signaling proteins, protein hormones, and the membrane receptors that make up roughly 60% of today’s drug targets—share an inconvenient trait: they’re often poorly soluble. Push their concentration even slightly too high, and they clump and lose function. That same solubility problem has long limited chemical protein synthesis, where multiple peptide fragments must be stitched together at relatively high concentrations. One hydrophobic or aggregation‑prone segment is enough to stall the entire process.
A new study from researchers at ETH Zurich may offer a way around that long‑standing barrier. In their paper published in Science, “Zwitterionic organoboron complexes for overcoming the concentration barrier in chemical protein synthesis,” the team reported a boron‑based ligation strategy that enables protein fragment coupling at concentrations up to 1,000‑fold lower than traditional methods.
The core challenge, the authors noted, is that conventional carbon‑based coupling chemistry is a slow process. In cells, enzymes accelerate peptide bond formation with extraordinary speed. In the lab, chemists must compensate for slower reactions by driving concentrations unnaturally high—precisely the conditions that cause many biologically important proteins to fall out of solution. “With purely carbon‑based systems, we hit a fundamental limit of reaction rates,” said senior author Jeffrey Bode, PhD, of ETH Zurich, in a press release. “By extending into previously unexplored boron-based reagents, we enter a realm in which even challenging reactions coupling large biological molecules together can take place extremely quickly.”
The ETH team’s solution centers on potassium acyltrifluoroborates (KATs), a class of organoboron reagents known for fast, chemoselective amide‑bond formation. Until now, KATs couldn’t be used in automated peptide synthesis because they lacked a protecting group stable enough to survive the harsh acidic conditions of solid‑phase synthesis. The breakthrough came with the development of chiral, zwitterionic organoboron complexes that “mask” KATs during synthesis and can be cleanly deprotected afterward. “We synthesized C-terminal KAT peptides and demonstrated KAT ligation at micromolar concentrations for the convergent synthesis of the aggregation-prone programmed death ligand 2 (PD-L2) immunoglobulin V domain,” the authors wrote.
The ability to access such proteins more reliably could have broad implications for drug discovery, including the development of next‑generation biologics and antibody–drug conjugates, which rely on precise chemical handles and often involve difficult‑to‑synthesize domains. Looking ahead, the team sees opportunities to expand the chemical toolbox even further. The method allows chemists to introduce unnatural amino acids at defined positions, enabling site‑specific conjugation strategies used in targeted cancer therapies.
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