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1.
Nat Commun ; 15(1): 3302, 2024 Apr 24.
Article in English | MEDLINE | ID: mdl-38658535

ABSTRACT

Uncontrolled secretion of ECM proteins, such as collagen, can lead to excessive scarring and fibrosis and compromise tissue function. Despite the widespread occurrence of fibrotic diseases and scarring, effective therapies are lacking. A promising approach would be to limit the amount of collagen released from hyperactive fibroblasts. We have designed membrane permeant peptide inhibitors that specifically target the primary interface between TANGO1 and cTAGE5, an interaction that is required for collagen export from endoplasmic reticulum exit sites (ERES). Application of the peptide inhibitors leads to reduced TANGO1 and cTAGE5 protein levels and a corresponding inhibition in the secretion of several ECM components, including collagens. Peptide inhibitor treatment in zebrafish results in altered tissue architecture and reduced granulation tissue formation during cutaneous wound healing. The inhibitors reduce secretion of several ECM proteins, including collagens, fibrillin and fibronectin in human dermal fibroblasts and in cells obtained from patients with a generalized fibrotic disease (scleroderma). Taken together, targeted interference of the TANGO1-cTAGE5 binding interface could enable therapeutic modulation of ERES function in ECM hypersecretion, during wound healing and fibrotic processes.


Subject(s)
Cicatrix , Collagen , Fibroblasts , Wound Healing , Zebrafish , Humans , Animals , Fibroblasts/metabolism , Fibroblasts/drug effects , Collagen/metabolism , Wound Healing/drug effects , Cicatrix/metabolism , Cicatrix/pathology , Cicatrix/drug therapy , Skin/metabolism , Skin/pathology , Skin/drug effects , Fibrosis , Peptides/pharmacology , Peptides/metabolism , Endoplasmic Reticulum/metabolism , Endoplasmic Reticulum/drug effects , Scleroderma, Systemic/metabolism , Scleroderma, Systemic/drug therapy , Scleroderma, Systemic/pathology , Extracellular Matrix/metabolism , Extracellular Matrix/drug effects
2.
Molecules ; 27(19)2022 Oct 07.
Article in English | MEDLINE | ID: mdl-36235193

ABSTRACT

Herein, the design and synthesis of peptide-drug conjugates (PDCs) including different variants of the cell-penetrating peptide sC18 is presented. We first generated a series of novel sequence mutants of sC18 having either amino acid deletions and/or substitutions, and then tested their biological activity. The effects of histidine substituents were found to be not meaningful for sC18 uptake and cell selectivity. Moreover, building a nearly perfect amphipathic structure within a shortened sC18 derivative provided a peptide that was highly membrane-active, but also too cytotoxic. As a result, the most promising analog was sC18ΔE, which stands out due to its higher uptake efficacy compared to parent sC18. In the last set of experiments, we let the peptides react with the cytotoxic drug doxorubicin by Thiol-Michael addition to form novel PDCs. Our results indicate that sC18ΔE could be a more efficient drug carrier than parent sC18 for biomedical applications. However, cellular uptake using endocytosis and resulting entrapment of cargo inside vesicles is still a major critical step to overcome in CPP-containing peptide-drug development.


Subject(s)
Antineoplastic Agents , Cell-Penetrating Peptides , Antineoplastic Agents/pharmacology , Cell-Penetrating Peptides/chemistry , Doxorubicin/pharmacology , Drug Carriers/chemistry , Drug Delivery Systems , Histidine , Sulfhydryl Compounds
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