Our Investment In What Nature Thought to Make – Unnatural Products

• AI-enhanced platform creates entirely new drugs by engineering synthetic molecules to mimic nature’s macrocycles

By Brent MacDonald – Partner at Rising Tide

Established technologies only address a fraction of the drug targets that could have an impact on human health. Unnatural Products (UNP) has developed a machine learning platform to iteratively optimize macrocycle design and predict their passive permeability into cells. The Company’s focus is on the ‘hit-to-lead’ portion of drug development. Essentially, UNP takes an existing hit compound and applies silicon design tools to it alongside machine learning-powered permeability models. Macrocycles that score highly are synthesized and analyzed in vitro through Parallel Artificial Membrane Permeability Assays (PAMPA) and binding assays. This process is performed iteratively until a lead compound is identified. UNP’s unique platform closely marries prediction with experiment. This rapid, intelligent learning loop has allowed UNP to solve key challenges, such as cell permeability, which have previously been roadblocks in macrocycle development. Though currently focused on select oncology targets, this technology can be applied to a wide variety of urgent clinical needs, such as inflammatory diseases. Further, UNP’s AI-enhanced technology platform creates entirely new drugs by engineering passively permeable, macrocyclic peptides that access traditionally undruggable targets – 70% of drug targets are too complex for small molecules and beyond the reach of biologics.

The Company announced a research discovery collaboration with BridgeBio Pharma to target rare diseases with potential oncology applications. Both companies are working to turn the initial chemical series from exciting academic tool compounds into promising therapeutics. In addition, Merck & Co. signed a $220 million macrocyclic peptide deal with Unnatural Products after hailing the ‘next wave of drug discovery’. Merck has previously referred to macrocyclic peptides as the “Goldilocks” chemical modality because “their intermediate size combines the favorable properties of both small molecules and biologics.” Unnatural Products revealed that it has raised $32 million in Series A funding, which will be utilized to push UNP's technological platform forward and broaden the Company's scope beyond cancer to include new markets. See the funding press release here.

Why We Are Excited:

There are several companies focused on discovering macrocycles for specific drug targets (hits). However, most of these companies face the same challenge once they have identified a hit: cell permeability. Unnatural Products (UNP) has developed a machine learning platform to iteratively optimize macrocycle design and predict their passive permeability into cells. The Company’s focus is on the ‘hit-to-lead’ portion of drug development. Essentially, UNP takes an existing hit compound and applies in silico design tools to it alongside Machine Learning-powered permeability models. UNP’s unique platform closely marries prediction with experiment. This rapid, intelligent learning loop has allowed UNP to solve key challenges, such as cell permeability, which have previously been the roadblock in macrocycle development. Though currently focused on select oncology targets, this technology can be applied to a wide variety of urgent clinical needs, such as inflammatory diseases. We wholeheartedly endorse the Company's goal of "imbuing targeted and designed synthetic macrocycles with the favorable drug-likeness of evolved macrocycles found in nature" through the use of its chemistry and AI-driven platform.

Disclaimer: Rising Tide Fund Managers, LLC and its affiliates (“Rising Tide” or “We”) is a United States venture capital firm investing primarily in the information technology and healthcare/life sciences markets. Over the last 35 years, we have partnered with family funds, high-impact investors, and strategic partners to help launch and expand startups in a variety of industries across three continents. We are dedicated to cooperating with our entrepreneurs at all stages: from financing to leveraging our international networks to facilitating exits by design. The portfolio companies described herein do not represent all the portfolio companies purchased, sold, or recommended for portfolios advised by Rising Tide. The reader should not assume that an investment in the portfolio companies identified were or will be profitable. Past performance is not indicative of future results. Investors should be aware that a loss of investment is possible. For more information, visit www.rtf.vc