Controlling Polymer Morphologies by Intramolecular and Intermolecular Dynamic Covalent Iron(III)/Catechol Complexation-From Polypeptide Single Chain Nanoparticles to Hydrogels.

Responsive biomaterials, tunable from the molecular to the macroscopic scale, are attractive for various applications in nanotechnology. Herein, a long polypeptide chain derived from the abundant serum protein human serum albumin is cross-linked by dynamic-coordinative iron(III)/catechol bonds. By tuning the binding stoichiometry and the pH, reversible intramolecular folding into polypeptide nanoparticles with controllable sizes is achieved. Moreover, upon varying the stoichiometry, intermolecular cross-links become predominant yielding smart and tunable macroscopic protein hydrogels. By adjusting the intra- and intermolecular interactions, biocompatible and biodegradable materials are formed with varying morphologies and dimensions covering several lengths scales featuring rapid gelation without toxic reagents, fast and autonomous self-healing, tunable mechanical properties, and high adaptability to local environmental conditions. Such material characteristics can be particularly attractive for tissue engineering approaches to recreate soft tissues matrices with highly customizable features in a fast and simple fashion.

Supramolecular Mechanism of Viral Envelope Disruption by Molecular Tweezers.

Broad-spectrum antivirals are powerful weapons against dangerous viruses where no specific therapy exists, as in the case of the ongoing SARS-CoV-2 pandemic. We discovered that a lysine- and arginine-specific supramolecular ligand (CLR01) destroys enveloped viruses, including HIV, Ebola, and Zika virus, and remodels amyloid fibrils in semen that promote viral infection. Yet, it is unknown how CLR01 exerts these two distinct therapeutic activities. Here, we delineate a novel mechanism of antiviral activity by studying the activity of tweezer variants: the "phosphate tweezer" CLR01, a "carboxylate tweezer" CLR05, and a "phosphate clip" PC. Lysine complexation inside the tweezer cavity is needed to antagonize amyloidogenesis and is only achieved by CLR01. Importantly, CLR01 and CLR05 but not PC form closed inclusion complexes with lipid head groups of viral membranes, thereby altering lipid orientation and increasing surface tension. This process disrupts viral envelopes and diminishes infectivity but leaves cellular membranes intact. Consequently, CLR01 and CLR05 display broad antiviral activity against all enveloped viruses tested, including herpesviruses, Measles virus, influenza, and SARS-CoV-2. Based on our mechanistic insights, we potentiated the antiviral, membrane-disrupting activity of CLR01 by introducing aliphatic ester arms into each phosphate group to act as lipid anchors that promote membrane targeting. The most potent ester modifications harbored unbranched C4 units, which engendered tweezers that were approximately one order of magnitude more effective than CLR01 and nontoxic. Thus, we establish the mechanistic basis of viral envelope disruption by specific tweezers and establish a new class of potential broad-spectrum antivirals with enhanced activity.

Sequence Programming with Dynamic Boronic Acid/Catechol Binary Codes.

The development of a synthetic code that enables a sequence programmable feature like DNA represents a key aspect toward intelligent molecular systems. We developed herein the well-known dynamic covalent interaction between boronic acids (BAs) and catechols (CAs) into synthetic nucleobase analogs. Along a defined peptide backbone, BA or CA residues are arranged to enable sequence recognition to their complementary strand. Dynamic strand displacement and errors were elucidated thermodynamically to show that sequences are able to specifically select their partners. Unlike DNA, the pH dependency of BA/CA binding enables the dehybridization of complementary strands at pH 5.0. In addition, we demonstrate the sequence recognition at the macromolecular level by conjugating the cytochrome c protein to a complementary polyethylene glycol chain in a site-directed fashion.