Biosynthonics: Charting the Future Role of Biocatalysis and Metabolic Engineering in Drug Discovery

Abstract

Ironic as it sounds, the pharmaceutical industry is ailing. Despite doubling their R&D expenditures over the past decade, innovator drug companies have struggled to increase their annual drug approval rates. Worse still, candidate attrition rates and development times actually rose during this period. It now costs well in excess of a billion dollars and takes over a decade to discover and develop a new drug. A variety of prognostications have been made regarding the future course that the pharmaceutical industry might take, but none has been as controversial as the suggestion that small-molecule drugs could disappear by 2030. Rest assured that these claims could not be further from the truth. Herein, I outline how biocatalysis and metabolic engineering could drive the next wave of innovation in small-molecule drug discovery. The recent past has witnessed staggering developments in analytical chemistry, genome sequencing and assembly, flow chemistry, chemi-and bioinformatics, metabolic engineering and synthetic chemistry, as well as exponential improvements in the raw computing power that is available for drug research; integrating these parallel innovations into a single platform could translate a vastly higher number of smallmolecule drugs to the bedside. I term this integrated approach as "biosynthonics". Many of its individual elements are already in use drug discovery and development, albeit in a scattered manner, and despite the substantial progress that has occurred in each individual domain, a lot still remains to be achieved if biosynthonics is to become a broad platform for generating focused libraries of natural product-like molecules. It is hoped that this article spurs debate and future collaborations toward achieving these goals, which, if successful, would undoubtedly improve small-molecule R&D productivity.

Harnessing emerging paradigms in chemical engineering to accelerate the development of pharmaceutical products

“…The very properties that make natural products more likely to bind to a target in the body also create steep challenges for discovering, developing, and manufacturing them. [19] The costs associated with the latter two activities, in particular, often run into the hundreds of millions of dollars and pharmaceutical companies have consistently struggled to develop economical routes to manufacture pharmaceutically relevant natural products. [20,21] However, the decision of the pharmaceutical industry to move away from natural products chemical space as a source of drugs in favour of more manufacturable molecules appears to have been a questionable one.…”

“…To this end, we advanced the concept of biosynthonics five years ago. [19] The term's etymological roots can be traced to the concept of a synthon, which is defined as a structural unit within a molecule that is the product of a specific synthetic operation, or, quite simply, a synthetic building block. [27] Consequently, a biosynthon is a structural building block that is the product of a biosynthetic or biocatalytic reaction.…”

“…As was alluded to earlier, the biosynthesis of most pharmacoactive secondary metabolites can be divided into two distinct phases: scaffold assembly and diversityoriented functionalization. [12,13,19] Scaffolds commonly are products of synthases and reactions in the diversification phase are typically catalyzed by cytochrome P450 monooxygenases and esterifying enzymes such as acyltransferases. Owing to this unique scheme, several intermediates in the metabolic pathway, especially latter ones, closely resemble the final product and exhibit very similar physicochemical properties that are of consequence in the development of a suitable drug formulation.…”

Towards Precision Engineering of Canonical Polyketide Synthase Domains: Recent Advances and Future Prospects

“…mPKS engineering strategies themselves have evolved over the past decades, initially relying heavily on domain swaps, but now relying more on targeted, semi-rational and high-throughput approaches [ 2 , 6 , 28 , 29 , 30 ]. Finally, visions for high-throughput synthetic biology platforms have been described, using computational resources and automated microbiology to screen large quantities of yet-unexpressed natural products [ 31 ]. Achievement of such platforms could usher in a golden age of synthetic biology.…”

Cheminformatic Analysis of Antimalarial Chemical Space Illuminates Therapeutic Mechanisms and Offers Strategies for Therapy Development

“…7 A global health catastrophe could be at hand just as our drug arsenal is at its thinnest. 8 New antimalarial therapies will soon be required, 9 but the current state of antimalarial drug development points to an uncertain future. Antimalarial hits are presently identified using highthroughput whole-cell assays with the parasite itself, protein kinases activity assays, or through functional genomics.…”