A solid phase approach to PDMP analogs: A general strategy for combinatorial library

The present work reports the first solid phase synthesis of biologically interesting D-threo-l-phenyl-2- decanoylamino-3-morpholino-l-propanol （D-threo-PDMP） derivatives. This synthetic strategy includes facile preparation of versatile azido intermediate （5） in a relatively short sequence and the subsequent derivatization of 5, which led to a series of sulfonamide, urea and heterocycle substituted PDMP analogs （10 and 10＇）. With this method, a 5280-member compound library has been successfully built by IRORI Nanokan system.

Screened peptides from one-bead one-compound technique extend half-life of peptide drugs in circulation through binding to albumin

Peptide drugs are known for their high biological safety.However,compared with small molecule drugs,peptide drugs are easily oxidized and hydrolyzed as well as short in half-life.Herein,inspired by the long circulation of albumin in blood,we screened albumin binding peptides(ABPs)from a one-bead one-compound(OBOC)peptide library to increase the half-life of peptide drugs.Beads displaying random peptides were screened using fluorescent labeled human serum albumin.Fluorescent beads with specific binding to albumin were isolated for sequencing.The selected ABPs can effectively bind to albumin,thus possessing the long circulation of albumin.The dissociation constant(K_(D))of ABPs to albumin is up to 1×10^(-8)mol/L.Once one of ABPs(ABP2)was coupled to triptorelin,the circulation half-life of triptorelin in mice was significantly prolonged to 263.50 h much longer than that of triptorelin alone(179.07 h).In addition,the combination therapy using ABP-conjugated triptorelin and doxorubicin(DOX)can effectively inhibit the proliferation of tumor cells in mice.The OBOC screening strategy and resulting ABPs showed great potential for enhancing the delivery efficiency of peptide drugs.

Tailoring combinatorial lipid nanoparticles for intracellular delivery of nucleic acids, proteins,and drugs

Lipid nanoparticle(LNP)-based drug delivery systems have become the most clinically advanced non-viral delivery technology.LNPs can encapsulate and deliver a wide variety of bioactive agents,including the small molecule drugs,proteins and peptides,and nucleic acids.However,as the physicochemical properties of small-and macromolecular cargos can vary drastically,every LNP carrier system needs to be carefully tailored in order to deliver the cargo molecules in a safe and efficient manner.Our group applied the combinatorial library synthesis approach and in vitro and in vivo screening strategy for the development of LNP delivery systems for drug delivery.In this Review,we highlight our recent progress in the design,synthesis,characterization,evaluation,and optimization of combinatorial LNPs with novel structures and properties for the delivery of small-and macromolecular therapeutics both in vitro and in vivo.These delivery systems have enormous potentials for cancer therapy,antimicrobial applications,gene silencing,genome editing,and more.We also discuss the key challenges to the mechanistic study and clinical translation of new LNP-enabled therapeutics.

Zn^(2+) loading as a critical contributor to the circ_0008553-mediated oxidative stress and inflammation in response to PM_(2.5) exposures

Inflammation is a major adverse outcome induced by inhaled particulate matter with a diameter of≤2.5μm(PM_(2.5)),and a critical trigger ofmost PM_(2.5) exposure-associated diseases.However,the key molecular events regulating the PM_(2.5)-induced airway inflammation are yet to be elucidated.Considering the critical role of circular RNAs(circRNAs)in regulating inflammation,we predicted 11 circRNAs that may be involved in the PM_(2.5)-induced airway inflammation using three previously reportedmiRNAs through the starBasewebsite.A novel circRNA circ_0008553 was identified to be responsible for the PM_(2.5)-activated inflammatory response in human bronchial epithelial cells(16HBE)via inducing oxidative stress.Using a combinatorial model PM_(2.5) library,we found that the synergistic effect of the insoluble core and loaded Zn^(2+)ions at environmentally relevant concentrations was the major contributor to the upregulation of circ_0008553 and subsequent induction of oxidative stress and inflammation in response to PM2.5 exposures.Our findings provided new insight into the intervention of PM_(2.5)-induced adverse outcomes.