Getting drugs into cells is hard work, and even therapeutic candidates with excellent affinity and specificity will be unsuccessful if they cannot reach their target. To this end, medicinal chemists have relied heavily on a heuristic known as the ‘rule of five’, first described by Christopher Lipinski and colleagues at Pfizer in 2001 (ref. 1), which establishes thresholds for size, hydrophobicity and other chemical properties associated with good bioavailability and cell permeability.

Cameron Pye. Credit: Unnatural Products

But, as the saying goes, rules were made to be broken — and many promising drug candidates reside beyond the confines of these guidelines. “Some of them were more rules of thumb to keep things easy,” says Cameron Pye, CEO and co-founder of Santa Cruz, California-based Unnatural Products.

Pye and Joshua Schwochert, the company’s CSO and co-founder, are betting heavily on the clinical potential of a family of molecules known as macrocyclic peptides. These molecules, which are composed of amino acids assembled into a ring-shaped structure, are larger than typical small-molecule drugs and in many cases do not comply with the rule of five. Nevertheless, evolution has given rise to several examples of naturally occurring macrocyclic peptides with potent therapeutic properties, including the fungus-derived immunosuppressant drug cyclosporine.

Some macrocyclic peptides have demonstrated a remarkable capacity for rapid gut absorption and cellular uptake, despite their relatively high molecular weight and the presence of a polar peptide backbone that would normally impede passage through cell membranes. Jan Kihlberg, a medicinal chemist specializing in ‘beyond-rule-of-five’ drugs at Uppsala University, says that such compounds are sometimes described as ‘molecular chameleons’ — changing their structural conformation in response to their chemical environment. For example, cyclosporine is typically unfurled and flat in solution, but undergoes a rearrangement at the cell surface. “While crossing the membrane, it folds and forms these intramolecular hydrogen bonds, crosses the membrane, and then it unfolds on the other side,” says Kihlberg.

This structural lability is also advantageous for targeting proteins that do not offer ready purchase for conventional small-molecule drugs. “These larger, more complex molecules can just target more shallow and diffuse interaction spaces,” explains Pye. This is particularly useful when the goal is to disrupt specific protein–protein interactions that contribute to disease pathology — for example, in the context of the aberrant cellular signaling pathways underlying tumor growth and invasion. Collectively, these properties offer the potential for orally delivered compounds that can achieve antibody-like levels of affinity and specificity for both intracellular and extracellular targets.

Unnatural Products was born in the lab of University of California at Santa Cruz chemist Scott Lokey, who is now a consultant for the company. Several fully synthetic macrocyclic peptide drugs are already in the clinic, but the discovery and development of such compounds has proven laborious and time-consuming. As graduate students in Lokey’s lab, Schwochert and Pye focused on developing strategies to accelerate screening for macrocyclic peptides that can effectively bind challenging targets while also delivering important properties such as high solubility and bioavailability. This included the use of assays based on phage display and DNA-encoded libraries, which make it possible to rapidly screen millions or billions of different macrocyclic peptides at a time.

The two students soon recognized the commercial potential in their work. “Suddenly, we were discovering thousands of cell-permeable cyclic peptides in a single experiment,” says Pye. “We were like, ‘This is hard, but actually not that hard’.” He and Schwochert would go on to found Unnatural Products in 2017, shortly after receiving their PhDs. The first few years were tough, but in 2019 the company received $6 million in seed funding, enabling it to substantially grow its operation. In late 2023, the company received a further infusion of $23 million in series A funding.

In parallel, the past several years have seen growing interest from the pharmaceutical industry in developing more unconventional, beyond-rule-of-5 drug candidates. As examples, Kihlberg points to promising clinical-stage macrocyclic peptide molecules developed by Chugai and Merck, which are both designed to hit high-value clinical targets: the oncogene KRAS and the cholesterol-regulating protein PCSK9, respectively. “I’d say most companies now realize that this is a field you might want to be in,” says Kihlberg.

For Unnatural Products, this enthusiasm has also manifested as investments and collaborations with pharma partners. In 2021, it announced a drug discovery partnership with Palo Alto, California-based rare genetic disease specialists BridgeBio Pharma, and Pye says this has already yielded some promising drug candidates with excellent selectivity and femtomolar-range affinity. “This was a never-touched-before protein from a targeting perspective,” says Schwochert. “Partially because of the rare disease angle, partially because there was this nigh-impossible selectivity angle that needed to be overcome.” And in January 2024, Merck signed a deal with the company that could be worth up to $220 million. The specific focus of this collaboration has not been disclosed, but Pye describes it as “a very challenging, very well-known protein target in the oncology space.” The company is also building its own internal clinical pipeline alongside these collaborative discovery programs.

Rather than settling on a single discovery platform, researchers at Unnatural Products are still exploring a range of different display and screening technologies. Pye notes that each method has its own strengths and limitations. For example, methods such as mRNA display and phage display rely on natural translational machinery to produce macrocyclic peptides, which makes it difficult to incorporate unnatural amino acids and thus limits the chemical space that can be explored in a screen. In contrast, DNA-encoded libraries rely on chemical synthesis and can thus incorporate greater chemical diversity, although the sizes of these libraries tend to be smaller overall. Pye says he is particularly bullish on this latter technology, and in 2023 the company published a collaborative study with scientists at Shanghai-based WuXi AppTec in which DNA-encoded libraries were used to identify a cell-permeable macrocyclic peptide that efficiently disrupts the interaction between the tumor suppressor protein p53 and its inhibitor MDM2 at nanomolar concentrations.

There is still a lot of uncharted terrain in this area of drug discovery. But Kihlberg is hopeful about the company’s prospects given its origins with the Lokey group, which is known for its expertise in the domain of cyclic peptides. “It’s not only what works that you need to know — you also need to know what doesn’t work, and that’s never in the literature,” he says. “Coming from a group that’s got a long experience in this area gives them that knowledge.”

And the rewards for developing a robust macrocyclic peptide development platform could be considerable. For example, Pye and Schwochert see the potential to develop pill-based alternatives to antibody-based drugs that require intravenous infusion, or to generate snugly binding ‘molecular glue’ compounds that trap proteins in a particular conformation or strengthen protein–protein interactions rather than disrupting them2. “I think that a lot of the low-hanging fruit is plucked, and that to reach for those higher branches, we’re going to need more complex chemical matter,” says Pye. “We’re here to work with it.”