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

Proteolytic Unlocking of Ultrastable Twin-Acylhydrazone Linkers for Lysosomal Acid-Triggered Release of Anticancer Drugs

Targeted prodrugs exploiting cleavable linkers capable of responding to endogenous stimuli have increasingly been explored for cancer therapy. Successful application of these prodrug designs relies on the manipulation of both stability and responsiveness of the cleavable linkers, which, however, are difficult to be finely regulated, particularly for acid-responsive acylhydrazone bonds. Here we developed a new class of peptide-bridged twin-acylhydrazone linkers (PTA linkers) displaying both an ultrahigh stability and a rapid responsivenesshighly stable in neutral and acidic conditions due to the effect of cooperativity between the two acylhydrazone bonds, easily cleavable in acidic conditions after enzymatically triggered unlocking of the two bonds. Moreover, our study shows the design of PTA-linked prodrugs and the proof-of-concept application of the PTA linkers for site-specific release of anticancer drugs into cancer cells

MOESM1 of Self-reported questionnaire survey on the prevalence and symptoms of adverse food reactions in patients with chronic inhalant diseases in Tangshan city, China

Additional file 1. Self-reported questionnaire survey on the prevalence and symptoms of food adverse reactions in patients with asthma, rhinitis and conjunctivitis. The questionnaire was developed referring to [1]