RT Journal Article
SR Electronic
T1 Weak Microbial Metabolites: a Treasure Trove for Using Biomimicry to Discover and Optimize Drugs
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 343
OP 349
DO 10.1124/molpharm.120.000035
VO 98
IS 4
A1 Zdenek Dvorak
A1 Max Klapholz
A1 Thomas P. Burris
A1 Benjamin P. Willing
A1 Antimo Gioiello
A1 Roberto Pellicciari
A1 Francesco Galli
A1 John March
A1 Stephen J. O’Keefe
A1 R. Balfour Sartor
A1 Chang H. Kim
A1 Maayan Levy
A1 Sridhar Mani
YR 2020
UL http://molpharm.aspetjournals.org/content/98/4/343.abstract
AB For decades, traditional drug discovery has used natural product and synthetic chemistry approaches to generate libraries of compounds, with some ending as promising drug candidates. A complementary approach has been to adopt the concept of biomimicry of natural products and metabolites so as to improve multiple drug-like features of the parent molecule. In this effort, promiscuous and weak interactions between ligands and receptors are often ignored in a drug discovery process. In this Emerging Concepts article, we highlight microbial metabolite mimicry, whereby parent metabolites have weak interactions with their receptors that then have led to discrete examples of more potent and effective drug-like molecules. We show specific examples of parent-metabolite mimics with potent effects in vitro and in vivo. Furthermore, we show examples of emerging microbial ligand-receptor interactions and provide a context in which these ligands could be improved as potential drugs. A balanced conceptual advance is provided in which we also acknowledge potential pitfalls—hyperstimulation of finely balanced receptor-ligand interactions could also be detrimental. However, with balance, we provide examples of where this emerging concept needs to be tested.SIGNIFICANCE STATEMENT Microbial metabolite mimicry is a novel way to expand on the chemical repertoire of future drugs. The emerging concept is now explained using specific examples of the discovery of therapeutic leads from microbial metabolites.