Building upon Nature's Framework: Overview of Key Strategies Toward Increasing Drug-Like Properties of Natural Product Cyclopeptides and Macrocycles.

The pharmaceutical industry has focused mainly in the development of small-molecule entities intended for oral administration for the past decades. As a result, the majority of existing drugs address only a narrow range of biological targets. In the era of post-genomics, transcriptomics, and proteomics, there is an increasing interest on larger modulators of proteins that can span larger surfaces, access new therapeutic mechanisms of action, and provide greater target specificity. Traditional drug-like molecules developed using "rule-of-five" (Ro5) guidelines have been proven ineffective against a variety of challenging targets, such as protein-protein interactions, nucleic acid complexes, and antibacterial modalities. However, natural products are known to be effective at modulating such targets, leading to a renewed focus by medicinal chemists on investigating underrepresented chemical scaffolds associated with natural products. Here we describe recent efforts toward identification of novel natural cyclopeptides and macrocycles as well as selected medicinal chemistry strategies to increase drug-like properties or further exploration of their activity.