Orthogonal Cysteine-Penicillamine Disulfide Pairing for Directing the Oxidative Folding of Peptides.

Precise disulfide pairing in synthetic peptides usually is achieved using orthogonal protecting group strategies or relies on primary sequence manipulation. Orthogonal disulfide pairing technology should be promising for directing the rational folding of multicyclic peptides from the fully reduced peptides. Here, we report a discovery on the orthogonality between heterodisulfide pairing of cysteine (Cys) and penicillamine (Pen) and formation of Cys-Cys/Pen-Pen homodisulfides. The orthogonal Cys-Pen disulfide pairing can be exploited for highly selective production of certain (multi)cyclic structures (or even a sole structure without isomers) through direct oxidation in air or thiol-disulfide exchanges in redox media. This strategy makes rational folding of multicyclic peptides without protecting groups, sequence manipulation, and complex synthetic reactions a reality, thus providing invaluable assets to peptide communities, and should greatly benefit the development of multicyclic peptide therapeutics and ligands.

Extraordinary modulation of disulfide redox-responsiveness by cooperativity of twin-disulfide bonds.

Disulfide bonds have frequently been incorporated into synthetic materials to promote sensitivity of the systems towards different redox environments. Although many strategies have been developed to rationally tune the stability of disulfide linkers, methods to tune their responsiveness towards different redox environments remain elusive. In this work we have developed and explored a disulfide linker bearing two independent disulfide bonds, referred to as a twin-disulfide linker. We have demonstrated that the twin-disulfide linker displays an ultrahigh stability at lower concentrations of reducing agent or in weakly reducing environments without a significant compromise in the sensitivity of its response to highly reducing environments such as cytoplasm, a feature that is in remarkable contrast to the traditional single disulfide bonds. Such an extraordinary responsiveness arises from the cooperativity of the twin-disulfide bonds, which should be of particular interest for applications such as controlled drug delivery and sensing, because relatively large differences in disulfide stability in different redox environments is desired in these applications.

Exploring and exploiting dynamic noncovalent chemistry for effective surface modification of nanoscale metal-organic frameworks.

Surface properties determine, to a great extent, the biologically relevant functions of various kinds of nanosized materials. Although the modification of the surface of traditional inorganic or polymeric nanoparticles can be routinely achieved through covalent or noncovalent manner or both, the surface modification of nanoscale metal-organic frameworks (nano-MOFs) is extremely challenging because of their rapid degradation in aqueous environments. In this work, we systematically studied the synergistic and dynamic noncovalent interactions between fluorescent probes and iron(III) carboxylate nano-MOFs (i.e., MIL-101-NH2 (Fe), one of the most prevalent MOFs used in drug delivery and imaging). We further examined the interplay between the surface binding of fluorescent probes and the degradation of MIL-101-NH2 (Fe) in aqueous medium. It was demonstrated that the surface binding of probes is not only of high affinity but also dynamic and nonsheddable, even during the degradation, a feature that is essentially different from the covalent conjugation. Subsequently, we developed a unique and straightforward strategy for the surface modification of MIL-101-NH2 (Fe) with polymer by exploiting the synergy of noncovalent interactions between functionalized copolymers and MIL-101-NH2 (Fe). We demonstrated that the binding of polymers onto MIL-101-NH2 (Fe) surface was very effective in aqueous solution and surprisingly nonsheddable during the process of degradation. Surface polymers can creep on the surface of MIL-101-NH2 (Fe), in a dynamic and real-time manner, to the new sites formed immediately after the degradation. In addition, the stability of MIL-101-NH2 (Fe) particles in aqueous environments can be improved to some extent by the surface polymer coating. The results presented herein constitute an important innovation for surface engineering of nano-MOFs, which would benefit the application of nano-MOFs as delivery systems in aqueous systems.