Article
Chemistry, Multidisciplinary
Kevin Van Holsbeeck, Baptiste Fischer, Simon Gonzalez, Charlene Gadais, Wim Versees, Jose C. Martins, Charlotte Martin, Alexandre Wohlkoenig, Jan Steyaert, Steven Ballet
Summary: RAS proteins play a crucial role in regulating intracellular signaling networks and mutations that stabilize their active state are associated with cancer development. The study investigated the potential of developing peptide mimetics to modulate RAS signaling by mimicking the complementarity-determining region 3 (CDR3) of the regulatory guanine nucleotide exchange factor (GEF) son of sevenless 1 (SOS1). Through optimization and conformational rigidification, CDR3 mimetics with half of the maximal activation potential of Nanobody14 (Nb14) were obtained, demonstrating the feasibility of modulating protein-protein interactions through structural mimicry of a paratope.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Article
Cardiac & Cardiovascular Systems
Xiaodan Zhong, Tao Wang, Yang Xie, Mengwen Wang, Wenjun Zhang, Lei Dai, Jinsheng Lai, Xiang Nie, Xingwei He, Thati Madhusudhan, Hesong Zeng, Hongjie Wang
Summary: This study demonstrates that aPC can protect against diabetic cardiomyopathy by maintaining YB-1 levels through the PAR1/EPCR signaling pathway, preventing its ubiquitination and degradation. Additionally, YB-1 exerts its protective effect by suppressing MEF2B transcription, highlighting the crucial role of the OTUB1/YB-1/MEF2B axis in diabetic cardiomyopathy.
FRONTIERS IN CARDIOVASCULAR MEDICINE
(2021)
Review
Biochemistry & Molecular Biology
Alessandra Monti, Luigi Vitagliano, Andrea Caporale, Menotti Ruvo, Nunzianna Doti
Summary: Protein-protein interfaces play crucial roles in pathophysiological pathways and are important targets for therapeutic compounds. However, identifying binding sites on protein surfaces and developing modulators of protein-protein interactions remain challenging due to their dynamic nature. Various strategies, including structural, computational, and combinatorial approaches, have been developed to characterize PPIs. Peptides are particularly potent and selective for inhibiting PPIs. This review discusses the impact of chemical peptide libraries in medicinal chemistry, focusing on recent applications, and explores the role of this methodology in the era of predictive approaches based on artificial intelligence in structural biology.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Chemistry, Multidisciplinary
Mathias Wendt, Rosa Bellavita, Alan Gerber, Nina-Louisa Efrem, Thirza van Ramshorst, Nicholas M. Pearce, Paul R. J. Davey, Isabel Everard, Mercedes Vazquez-Chantada, Elisabetta Chiarparin, Paolo Grieco, Sven Hennig, Tom N. Grossmann
Summary: This study designed beta-sheet mimetics targeting intracellular protein beta-catenin, effectively inhibiting the Wnt signaling pathway. The presented design strategy can support the development of inhibitors for other beta-sheet-mediated protein-protein interactions.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2021)
Article
Chemistry, Medicinal
Kumiko Tsuihiji, Eiji Honda, Kanehisa Kojoh, Shizue Katoh, Tomonori Taguri, Atsushi Yoshimori, Hajime Takashima
Summary: Currently, there is a rapid development of various pharmaceutical modalities, with a focus on targeting protein-protein interactions (PPIs). Cyclic peptides have gained attention as potential alternatives to antibody drugs due to their specificity and activity. However, they also present challenges such as oral availability and cell permeability. To overcome these difficulties, this study proposes a rational two-step strategy to design small-molecule compounds targeting PPIs. The strategy involves obtaining inhibitory cyclic peptides and converting them into small molecules using PepMetics(R) scaffolds. The researchers successfully generated small-molecule compounds with good inhibitory activity against CTLA-4. This approach is expected to be a useful method for designing small molecules targeting PPIs, even without structural information.
Review
Chemistry, Multidisciplinary
Laura K. Buckton, Marw N. Rahimi, Shelli R. McAlpine
Summary: Developing macrocyclic peptides that can reach intracellular targets is a significant challenge, and current chemical strategies can improve cell permeability, but often at the expense of biological activity.
CHEMISTRY-A EUROPEAN JOURNAL
(2021)
Article
Biochemistry & Molecular Biology
Hui-Min Zhou, Yun Ti, Hui Wang, Yuan-Yuan Shang, Ya-Peng Liu, Xiao-Ning Ni, Di Wang, Zhi-Hao Wang, Wei Zhang, Ming Zhong
Summary: The study suggests that CIDEC plays a critical role in diabetic cardiomyopathy (DCM) development, with CIDEC gene silencing significantly improving pathological features and cardiac function, involving the AMPKα signaling pathway as a potential mechanism. In vitro studies also show that CIDEC promotes collagen synthesis by interacting with AMPKα2 in the cell nucleus.
Article
Pharmacology & Pharmacy
Hui Lin, Le Guan, Liping Meng, Hiroyasu Uzui, Hangyuan Guo
Summary: SGLT1 is upregulated in diabetic cardiac tissues and high-glucose-induced cardiac fibroblasts. Its overexpression promotes cardiac fibroblast proliferation and collagen synthesis, while its silencing significantly alleviates cardiac fibrosis.
FRONTIERS IN PHARMACOLOGY
(2021)
Review
Endocrinology & Metabolism
Deng Pan, Lin Xu, Ming Guo
Summary: Protein kinase C (PKC) plays a crucial role in the development of diabetic microvascular complications by becoming activated under high-glucose conditions, leading to the accumulation of redox stress. This activation affects various types of cells in the microvasculature, resulting in changes in blood flow, microvascular permeability, extracellular matrix accumulation, basement thickening, and angiogenesis.
FRONTIERS IN ENDOCRINOLOGY
(2022)
Review
Biochemistry & Molecular Biology
Daiki Hayashi, Yasuhito Shirai
Summary: The drastic increase in the number of patients with diabetes and its complications is a global issue. Diabetic nephropathy, the leading cause of chronic kidney disease, significantly affects patients' quality of life and medical expenses. The activation of DGK to inhibit PKC activation shows potential therapeutic effect in ameliorating diabetic nephropathy.
Article
Biochemistry & Molecular Biology
Liding Zhao, Ya Li, Tian Xu, Qingbo Lv, Xukun Bi, Xianglan Liu, Guosheng Fu, Yunzeng Zou, Junbo Ge, Zhaoyang Chen, Wenbin Zhang
Summary: This study found that diabetes mellitus plays a significant role in aggravating chronic inflammation and promoting atherosclerosis, in conjunction with hyperlipidemia. The mechanism of action may involve the induction of immune maturation of dendritic cells, likely through the RAGE-TLR4-PKC β(1) signaling pathway.
MOLECULAR MEDICINE
(2022)
Article
Pharmacology & Pharmacy
Yan Yang, Haiming Xiao, Zeyuan Lin, Rui Chen, Shanshan Li, Chuting Li, Xiaohong Sun, Ziqing Hei, Wenyan Gong, Heqing Huang
Summary: CKIP-1 plays a nephroprotective role in diabetic nephropathy by regulating inflammation and its down-regulation exacerbates renal inflammatory fibrosis. Src kinase interacts with CKIP-1 and promotes its ubiquitination and protein degradation.
BIOCHEMICAL PHARMACOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Shulamit Fluss Ben-Uliel, Faten Habrat Zoabi, Moriya Slavin, Hadas Sibony-Benyamini, Nir Kalisman, Nir Qvit
Summary: Mitochondria are crucial for maintaining cellular energy metabolism and function, while Pink1 is a kinase that regulates mitochondrial function. In this study, a peptide targeting Pink1 was rationally designed and molecular probes with drug-like properties were developed to investigate Pink1's structure and function.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Endocrinology & Metabolism
Qixin Guo, Qingqing Zhu, Ting Zhang, Qiang Qu, Iokfai Cheang, Shengen Liao, Mengli Chen, Xu Zhu, Mengsha Shi, Xinli Li
Summary: This study identified potential immune biomarkers and molecular mechanisms of diabetic cardiomyopathy (DCM) by analyzing gene expression data and protein-protein interaction networks. EDN1 was found to play a key role in the development of DCM and may serve as a potential biomarker. Additionally, potential transcriptional regulatory factors and therapeutic drugs were identified.
FRONTIERS IN ENDOCRINOLOGY
(2022)
Editorial Material
Hematology
Jan A. Burger
Summary: The study reveals that MARCKS protein is differentially expressed in patients with chronic lymphocytic leukemia based on the mutation status of IGHV, and its expression and phosphorylation are linked to CLL cell migration through key signaling pathways. The findings were also confirmed in samples from patients treated with the BTK inhibitor acalabrutinib.
