Deep Tech Opportunity: There’s an exciting new way to put protein-like drugs inside cells

The modern phar­ma­copeia has generally been divided into small-molecule drugs that can easily cross the cell membrane and hit targets in the cytosol or the nucleus, and large-molecule drugs that are too big to slip through and that therefore work outside of cells, usually by modifying signaling between cells. Big, protein-sized drugs could be useful inside cells because smaller ones typically can’t interrupt the protein-protein inter­ac­tions that control so many aspects of cellular functioning — and that go wrong in myriad diseases. But researchers have had great difficulty (a) designing actual proteins or protein-scale drugs that can pass through the cell membrane, and (b) protecting them, once they’re inside, from the proteolytic enzymes that try to break them down.

Chicago-based Grove Biopharma has come up with an ingenious answer. The company has developed a way to package complex peptides — chains of amino acids — into globular protein-like structures that can travel through the membrane and resist proteolytic degradation. Once inside, these molecules can interact with the disordered protein targets involved in cancer and other conditions.

Grove calls these new molecules PLPs, for Precision-Linked Proteomimetics or Protein-Like Polymers. Each PLP is a customiz­able synthetic molecule consisting of a central chain with multiple side chains. If laid out flat, a PLP would resemble an array of bristles protruding from the head of a brush. Each bristle is a separate peptide, and the peptides are attached via linker units to backbone precursors, which, in turn, link up to form the head of the brush — the molecule’s spine (see figure). These versatile molecules represent ​“a fantastic evolution of biotech­nology,” says DCVC Bio’s Dr. Kiersten Stead.

One talent of PLPs is that they can respond dynamically to different targets and envi­ron­ments. When the peptide bristles are folded up, they create a kind of shell around the spine. The bristles’ highly polar electrical properties make the PLPs water-soluble in this state, meaning they can travel well in the aqueous envi­ron­ments inside and outside cells. But at the cell wall, the PLPs can unfold, exposing the low-polarity backbone, which allows the molecules to dissolve through the phos­pho­lipid bilayer that makes up the cell membrane. Once inside, the molecules fold up again for protection from proteolysis. The peptides themselves, along with any Grove-designed modules they may carry, are the important cargo. By virtue of their custom-designed amino acid sequences, they’re able to bind to specific proteins inside cells and block processes that can lead to disease.

As a case study, Dr. Nathan Gianneschi — the North­western University chemical biologist who is Grove’s scientific founder — showed in a mouse model that he could build a targeted PLP that blocks an important neuronal protein, VCP, from binding with mutant huntingtin protein. When natural peptides block this binding, it’s been shown to prevent the mito­chon­drial breakdown that char­ac­ter­izes Huntington’s disease.

And that’s just one example of the many kinds of protein-protein inter­ac­tions that could be modulated using PLPs. The company is already building PLPs that can interfere with the action of Myc, a family of tran­scrip­tion factor proteins that activate genes driving cell prolif­er­a­tion and are known to work overtime in most tumor cells. Grove also plans to develop a treatment for advanced prostate cancer by targeting AR-V7, an androgen receptor variant that continues to promote cell growth even in men who’ve had androgen-blocking therapy, and it’s studying whether PLPs can disrupt the inflam­ma­tory response that damages heart tissue after a myocardial infarction.

Stead says DCVC Bio has long wanted to invest in a company with a technology for binding to and inhibiting complex, disordered targets inside cells. ​“And when we came across Grove, we realized that we’d stumbled onto exactly that,” she says. ​“Grove’s peptides have known structures that bind to known targets. By themselves these peptides can’t get into cells. But when they’re configured into the Grove PLP format, all of a sudden they can become very specific and potent drugs.”