Biomedical Engineering Reference
In-Depth Information
6
Natural Products
in Drug Discovery
Guy T. Carter
CONTENTS
6.1 Introduction ........................................................................................................................... 89
6.2 Historical Perspective ........................................................................................................... 91
6.3 Antibiotics ............................................................................................................................. 92
6.4 Screening............................................................................................................................... 94
6.4.1 General Concepts..................................................................................................... 94
6.4.2 Whole Organism Screening..................................................................................... 95
6.4.3 Target-Based Screening ........................................................................................... 96
6.4.4 Dereplication............................................................................................................97
6.4.5 Screening Improvements ......................................................................................... 97
6.5 Optimization of Natural Product Leads................................................................................ 99
6.5.1 Semisynthesis........................................................................................................... 99
6.5.2 Improvements in Natural Products through Total Synthesis ................................. 100
6.5.3 Biosynthetic Modii cations .................................................................................... 100
6.5.3.1 Mutasynthesis......................................................................................... 101
6.5.3.2 Polyketide Synthase (PKS) Engineering................................................ 101
6.5.4 Structure-Activity Relationships........................................................................... 103
6.6 Concluding Remarks........................................................................................................... 105
Further Readings ............................................................................................................................ 105
6.1 INTRODUCTION
Natural products are loosely dei ned as secondary metabolites produced by living organisms.
These compounds are called “secondary” because they are generally not directly involved in the
primary processes of growth and development of the host. In the majority of cases the intrinsic bio-
logical functions of these secondary metabolites remain unknown. It has been postulated that such
secondary metabolites must have a vital role; otherwise evolutionary pressure would have purged
their encoding genes. One case where the role of the secondary metabolites seems reasonably
clear occurs in the microbial world. Antibiotics are natural products produced by microorganisms
that adversely affect other microbes, either through outright killing or inhibition of growth. The
producer microbe maintains a resistance mechanism that renders it insensitive to its own antibiotic.
Although the production of antibiotics for self-defense or to eliminate competition for resources
seems reasonable, there are still many unanswered questions about this process.
Natural products are conveniently classii ed into families of compounds according to their bio-
synthetic origin. For the purpose of this chapter we will consider the most prevalent biosynthetic
types as examples. Representative examples of the major biosynthetic classes are illustrated in
Figure 6.1. Perhaps the most biogenetically diverse family of natural products is the alkaloids,
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