A New Drug Discovery Paradigm: From Screening to Searching
By Devin Scannell, PhD, VP of Innovation for Zymergen
In late December 2021, the James Webb telescope was launched from Kourou, French Guiana. As described by NASA, the Webb telescope “will solve mysteries in our solar system, look beyond to distant worlds around other stars, and probe the mysterious structures and origins of our universe and our place in it.”1 It is an amazing achievement that has required advances in multiple technologies-as well as flawless execution-to bring about.
While this fascinating story is playing out hundreds of thousands of miles “above” us2, Zymergen has been undertaking a similar voyage of discovery to explore the galaxies of information below our feet. The number of microbial cells right here on earth exceeds the number of stars in the universe. The vast majority of microbial species have never been explored by science-or even grown in the lab-but encoded in each of their genomes is a wealth of genetic information. Of particular interest to Zymergen are groups of genes that encode molecules, sometimes called “natural products”, that have evolved to have highly diverse structures and to interact with proteins of all kinds. While our platform will stop short of solving the “origins of our universe and our place in it,” by accessing this reservoir of diverse novel chemistry, we believe we have a tool to develop drugs for diseases and targets that have stymied existing practices.
Last week at the 40th annual JP Morgan Healthcare Conference, Zymergen announced our new Drug Discovery business that leverages what is believed to be the world’s most advanced metagenomic database, our synthetic biology expertise, and proprietary data science and informatics tools.
Metagenomics: An untapped universe of chemical diversity
The two main “tools” in the therapeutic arsenal for the last three decades have been synthetic small molecules and monoclonal antibodies. While they have given us many needed drugs, they are notable for their drawbacks: Synthetic small molecules are frequently unable to engage challenging therapeutic targets, while monoclonals are restricted to the exterior of the cell. Consequently, many intracellular targets are today regarded as “undruggable” in the industry.
While new tools such as cell therapies are thankfully emerging, diverse, novel chemistry remains a throughline for drugging challenging intracellular targets. Small molecule modulators, protein degraders and antibody-drug conjugates to name a few, all rely on the right chemistry to be successful. Our metagenomics platform is one such source. By revealing the gene clusters that encode the wealth of novel, diverse molecules encoded in microbial genomes, our metagenomics platform has potential to enable the next generation of novel therapeutics.
“By revealing the gene clusters that encode the wealth of novel, diverse molecules encoded in microbial genomes, our metagenomics platform has potential to enable the next generation of novel therapeutics.”
Devin Scannell, VP of Innovation, Zymergen Drug Discovery
Today, screening a compound library to find molecules that engage a target of interest is a costly and often unsuccessful process. Typical high-throughput screening relies on large libraries of physical compounds (e.g., 104 – 1012), complex assay scale up, and frequently low hit rates due in part to high chemical redundancy. DNA-encoded libraries, mRNA display, and related technologies have enabled searching these large libraries, but have not resulted in appreciable hit rates.
Our technology completely changes the de novo screening process. Instead of complex large-scale physical screens, we use informatics and data science tools to rapidly search our database in silico. Using just the identity of the target protein, our algorithms search the DNA sequences in our proprietary metagenomics database and predict gene clusters with potential to encode molecules associated with the target of interest.
Take for example our recent work on MetAP-1. From the millions of biosynthetic gene clusters in our database, our search predicted 20 to be of highest interest. Of those 20, we tested two in vitro and confirmed activity against the human protein in both cases. The first of these we have named metapeptin, in honor of our metagenomics-enabled discovery process (and activity against MetAP-1), and we are now designing advanced analogs.
Perhaps most excitingly, because screening for us is a software exercise, we can easily re-run our algorithms and prioritize new molecules as our metagenomics database grows. Over time, we expect both the number of molecules we predict for a given target and the number of targets we can pursue will increase.
From synthetic chemistry to synthetic biology
A key historical challenge with molecules discovered from microbial sources using older methods has been producing the compound and making analogs-close chemical derivatives of the molecule-for testing. Traditionally, both of these are done using synthetic chemistry. Medicinal chemists often regard the “total synthesis” of these molecules as challenging, while generating analogs is often easier for smaller synthetic molecules.
We see our synthetic biology capabilities as a potential solution to both of these challenges. While synthetic chemistry is a core part of our workflow, synthetic biology brings new tools that can overcome previous challenges in chemical tractability. For example, we can choose to do semi-synthesis using microbial fermentation instead of total chemical synthesis for more complex molecules. Microbial fermentation is an area where Zymergen has deep expertise and experience. Similarly, we have developed tools such as “natural analoging” to access complex analogs (ie. natural product congeners) that may be challenging for synthetic chemistry. Ultimately, our approach is a collaboration between synthetic biology and synthetic chemistry that we think will be more than the sum of the parts.
“Looking beyond to distant worlds”
While the depth of our metagenomic information is always improving, the database is essentially created from a few teaspoons of soil. Each new teaspoon is another galaxy of information-and the opportunity to develop the next generation of medicines. Not deep in space, but all right under our feet. Please contact us if you want to join us on this journey.
Forward Looking Statements
This article contains “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995, as amended. Such forward-looking statements are based on the Company’s beliefs and assumptions and on information currently available to it on the date of this article. In some cases, you can identify these statements by forward-looking words such as “believe,” “may,” “can,” “will,” “potential,” “opportunity,” “expect,” or the negative or plural of these words or similar expressions. Forward-looking statements in this article include but are not limited to statements regarding the potential for our drug discovery business and the expectations for our metagenomics library. Forward-looking statements may involve known and unknown risks, uncertainties and other factors that may cause actual results, performance or achievements to be materially different from those expressed or implied by the forward-looking statements, including, but not limited to, risks relating to our ability to successfully commercialize or generate revenue from our products; our ability to develop or execute on our new strategic plan and our ability to reduce our operating costs and extend our cash runway. These and other risks are described more fully in the Company’s filings with the SEC, including the Company’s Quarterly Report on Form 10-Q for the quarter ended September 30, 2021, and other documents the Company subsequently files with the SEC. Except to the extent required by law, the Company undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made.