Author: Xun, Guoliang ; Atadja, Peter ; Vedadi, Masoud ; Lu, Chunliang ; Loppnau, Peter ; Arrowsmith, Cheryl H ; Zhao, Kehao ; Hajian, Taraneh ; Oyang, Counde ; Zhang, Hailong ; Brown, Peter J ; Allali-Hassani, Abdellah ; Xiao, Wen ; Luo, Xiao ; Zhu, Hugh Y ; Senisterra, Guillermo ; Yu, Zhengtian ; Li, Fengling ; Li, En ; Chau, Irene

Ubiquitin-like with PHD and RING finger domains 1 (UHRF1) is a multidomain protein that plays a critical role in maintaining DNA methylation patterns through concurrent recognition of hemimethylated DNA and histone marks by various domains, and recruitment of DNA methyltransferase 1 (DNMT1). UHRF1 is overexpressed in various cancers, including breast cancer. The tandem tudor domain (TTD) of UHRF1 specifically and tightly binds to histone H3 di- or trimethylated at lysine 9 (H3K9me2 or H3K9me3, respectively), and this binding is essential for UHRF1 function. We developed an H3K9me3 peptide displacement assay, which was used to screen a library of 44,000 compounds for small molecules that disrupt the UHRF1-H3K9me3 interaction. This screen resulted in the identification of NV01, which bound to UHRF1-TTD with a K_d value of 5 μM. The structure of UHRF1-TTD in complex with NV01 confirmed binding to the H3K9me3-binding pocket. Limited structure-based optimization of NV01 led to the discovery of NV03 (K_d of 2.4 μM). These well-characterized small-molecule antagonists of the UHRF1-H3K9me2/3 interaction could be valuable starting chemical matter for developing more potent and cell-active probes toward further characterizing UHRF1 function, with possible applications as anticancer therapeutics.

01 Apr 2006·Plastic and Reconstructive SurgeryQ2 · MEDICINE

Neurovascular Transfer Does Not Cause Skeletal Muscle Fiber Degeneration

Q2 · MEDICINE

Article

Author: William M. Kuzon ; James Demeester ; Jafar S. Hasan ; Kotaro Yoshimura ; Melanie G. Urbanchek

BACKGROUNDThe mechanisms responsible for the incomplete recovery of muscle function after microneurovascular transfer have not been fully determined. Because fiber degeneration and regeneration can impact muscle mechanical function, the authors tested the null hypothesis that ischemia-induced fiber degeneration is not responsible for the force deficits observed after neurovascular muscle transfer.METHODSRats were assigned to one of three groups: orthotopic, nonvascularized grafting of the extensor digitorum longus muscle (STD group); orthotopic, neurovascular transfer of the extensor digitorum longus muscle with no intraoperative ischemia (NV-0 group); or orthotopic, neurovascular transfer of the extensor digitorum longus muscle with 3 hours of intraoperative ischemia (NV-3 group). At 1 and 2 weeks, extensor digitorum longus muscle cross-sections were labeled for developmental myosin heavy chain isoforms, markers of fiber regeneration.RESULTSIn extensor digitorum longus muscles from animals in the STD group, many small cells strongly labeled for developmental myosin heavy chain were observed and identified as myoblasts, indicating recent muscle fiber necrosis with subsequent regeneration. Extensor digitorum longus muscles from rats in the NV-0 and NV-3 groups contained no cells labeled for developmental myosin heavy chain.CONCLUSIONSAfter neurovascular muscle transfer (with ischemia times up to 3 hours), ischemia-induced muscle fiber degeneration and regeneration does not occur. Muscle fiber degeneration is not responsible for the force deficits observed after microneurovascular skeletal muscle transfer.

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HIV Infections	Discovery	US	Idenix Pharmaceuticals LLC	-

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