Aberrant CXCR4/CXCL12 signaling is involved in many pathophysiological processes such as cancer and inflammatory diseases.A natural fragment of serum albumin,named EPI-X4,has previously been identified as endogenous p...Aberrant CXCR4/CXCL12 signaling is involved in many pathophysiological processes such as cancer and inflammatory diseases.A natural fragment of serum albumin,named EPI-X4,has previously been identified as endogenous peptide antagonist and inverse agonist of CXCR4 and is a promising compound for the development of improved analogues for the therapy of CXCR4-associated diseases.To generate optimized EPI-X4 derivatives we here performed molecular docking analysis to identify key interaction motifs of EPI-X4/CXCR4.Subsequent rational drug design allowed to increase the anti-CXCR4 activity of EPI-X4.The EPI-X4 derivative JM#21 bound CXCR4 and suppressed CXCR4-tropic HIV-1 infection more efficiently than the clinically approved small molecule CXCR4 antagonist AMD3100.EPI-X4 JM#21 did not exert toxic effects in zebrafish embryos and suppressed allergen-induced infiltration of eosinophils and other immune cells into the airways of animals in an asthma mouse model.Moreover,topical administration of the optimized EPI-X4 derivative efficiently prevented inflammation of the skin in a mouse model of atopic dermatitis.Thus,rationally designed EPIX4 JM#21 is a novel potent antagonist of CXCR4 and the first CXCR4 inhibitor with therapeutic efficacy in atopic dermatitis.Further clinical development of this new class of CXCR4 antagonists for the therapy of atopic dermatitis,asthma and other CXCR4-associated diseases is highly warranted.展开更多
Due to poor chemical robustness,superhydrophobic surfaces become susceptible to failure,especially in a highly oxidative environment.To ensure the longterm efficacy of these surfaces,a more stable and environmentally ...Due to poor chemical robustness,superhydrophobic surfaces become susceptible to failure,especially in a highly oxidative environment.To ensure the longterm efficacy of these surfaces,a more stable and environmentally friendly coating is required to replace the conventional salinization layers.Here,soottemplated surfaces with re‐entrant nanostructures are precoated with polydimethylsiloxane(PDMS)brushes.An additional nanometer‐thick lubricant layer of PDMS was then applied to increase chemical stability.The surface is superhydrophobic with a nanoscale liquid coating.Since the lubricant layer is thin,ridge formation is suppressed,which leads to low drop sliding friction and fast drop shedding.By introducing a bottom“reservoir”of a free lubricant as an oil source for self‐replenishing to the upper layer,the superhydrophobic surface becomes more stable and heals spontaneously in response to alkali erosion and O2 plasma exposure.This design also leads to a higher icing delay time and faster removal of impacting cooled water drops than for uncoated surfaces,preventing icing at low temperatures.展开更多
基金supported by the German Research Foundation(DFG)through the CRC1279supported by the DFG under Germany’s Excellence Strategy-EXC 2033-390677874-RESOLVby the Boehringer Ingelheim Foundation(Plus-3 Program)
文摘Aberrant CXCR4/CXCL12 signaling is involved in many pathophysiological processes such as cancer and inflammatory diseases.A natural fragment of serum albumin,named EPI-X4,has previously been identified as endogenous peptide antagonist and inverse agonist of CXCR4 and is a promising compound for the development of improved analogues for the therapy of CXCR4-associated diseases.To generate optimized EPI-X4 derivatives we here performed molecular docking analysis to identify key interaction motifs of EPI-X4/CXCR4.Subsequent rational drug design allowed to increase the anti-CXCR4 activity of EPI-X4.The EPI-X4 derivative JM#21 bound CXCR4 and suppressed CXCR4-tropic HIV-1 infection more efficiently than the clinically approved small molecule CXCR4 antagonist AMD3100.EPI-X4 JM#21 did not exert toxic effects in zebrafish embryos and suppressed allergen-induced infiltration of eosinophils and other immune cells into the airways of animals in an asthma mouse model.Moreover,topical administration of the optimized EPI-X4 derivative efficiently prevented inflammation of the skin in a mouse model of atopic dermatitis.Thus,rationally designed EPIX4 JM#21 is a novel potent antagonist of CXCR4 and the first CXCR4 inhibitor with therapeutic efficacy in atopic dermatitis.Further clinical development of this new class of CXCR4 antagonists for the therapy of atopic dermatitis,asthma and other CXCR4-associated diseases is highly warranted.
基金European Research Council(ERC)under the European Union's Horizon 2020 research and innovation program,Grant/Award Numbers:883631,DYNAMOGerman Research Society via the CRC 1194,Grant/Award Numbers:265191195,C07N。
文摘Due to poor chemical robustness,superhydrophobic surfaces become susceptible to failure,especially in a highly oxidative environment.To ensure the longterm efficacy of these surfaces,a more stable and environmentally friendly coating is required to replace the conventional salinization layers.Here,soottemplated surfaces with re‐entrant nanostructures are precoated with polydimethylsiloxane(PDMS)brushes.An additional nanometer‐thick lubricant layer of PDMS was then applied to increase chemical stability.The surface is superhydrophobic with a nanoscale liquid coating.Since the lubricant layer is thin,ridge formation is suppressed,which leads to low drop sliding friction and fast drop shedding.By introducing a bottom“reservoir”of a free lubricant as an oil source for self‐replenishing to the upper layer,the superhydrophobic surface becomes more stable and heals spontaneously in response to alkali erosion and O2 plasma exposure.This design also leads to a higher icing delay time and faster removal of impacting cooled water drops than for uncoated surfaces,preventing icing at low temperatures.
