Title :

Molecular Knots and Antimicrobial Peptides

Abstract :

Molecules with complex topologies, such as molecular links and knots, are often found in nature, but remain extremely difficult to synthesize using the current methods of chemistry. Over the past 30 years, the only strategy for the synthesis of molecular knots has been reliant on metal templation.1 Through our work on dynamic disulfide chemistry, we established that the hydrophobic effect can provide a powerful alternative synthetic strategy that enabled us to synthesize a variety of different knots, some of which had remained elusive until now: Hopf links,2,3 Solomon links,4 trefoil knots,5 and figure eight knots.4 In some cases, the hydrophobic effect overcomes electrostatic interactions between electron-rich and electron-deficient aromatic units, leading to the formation of unconventional structures that seem to contradict the current models of donor-acceptor interactions. A mechanism that succeeds in rationalizing and predicting their formation was proposed. This mechanism represents a major advance in understanding the role of hydrophobic effect in the assembly of complex architectures

In the second part of my talk, I will outline my current work on human defensins 5 and 6 (HD5-6), small (2-5 kDa) cysteine-rich host-defense peptides, which are key contributors to innate immunity and provides the first line of defense for detection and response to microbial invasion.6 Paneth cells protect the intestinal epithelium against infection and colonization of pathogenic or opportunistic microbes by secreting a mixture of antimicrobial peptides and proteins that includes HD5 and HD6. Although both peptides exhibit a common tertiary structure, they possess unique functional attributes. HD5 has broad-spectrum antibacterial activity in vitro. In contrast, HD6 provides only negligible antimicrobial activity in vitro but forms nanonets-like higher-order oligomeric structures that entrap bacteria in the intestinal lumen in order to prevent invasion. In the oxidized forms, both defensins contain three conserved and regiospecific intramolecular disulfide bonds. We explored the redox properties of these disulfide bonds and their role to maintain the peptides antimicrobial function. These peptides can interact with various metals, notably zinc,7 an important metal controlling the immune response.