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.
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.
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.
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 was 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 was achieved. Moreover, upon varying the stoichiometry, intermolecular cross-links became predominant yielding smart and tunable macroscopic protein hydrogels. By adjusting the intra-and intermolecular interactions, biocompatible and biodegradable materials were 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 could be particularly attractive for tissue engineering approaches to recreate soft tissues matrices with highly customizable features in a fast and simple fashion.
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 was cross-linked by dynamiccoordinative iron(III)/catechol bonds. By tuning the binding stoichiometry and the pH, reversible intramolecular folding into polypeptide nanoparticles with controllable sizes was achieved. Moreover, upon varying the stoichiometry, intermolecular cross-links became predominant yielding smart and tunable macroscopic protein hydrogels. By adjusting the intraand intermolecular interactions, biocompatible and biodegradable materials were 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 could be particularly attractive for tissue engineering approaches to recreate soft tissues matrices with highly customizable features in a fast and simple fashion.
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