更新于：2024-11-01

HGFA

更新于：2024-11-01

基本信息

别名

Hepatocyte growth factor activator、Hepatocyte growth factor activator long chain、Hepatocyte growth factor activator short chain

+ [4]

简介

Activates hepatocyte growth factor (HGF) by converting it from a single chain to a heterodimeric form.

关联

项与 HGFA 相关的药物

Caramcillin

靶点

HGFA x hepsin x matriptase

作用机制

HGFA 抑制剂 [+2]

在研机构-

原研机构-

在研适应症

细菌感染

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

VD-4162

靶点

HGFA x TMPRSS2 x hepsin

作用机制

HGFA 抑制剂 [+2]

在研机构

Washington University School of Medicine

原研机构

Washington University School of Medicine

在研适应症

肿瘤

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 HGFA 相关的临床结果

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100 项与 HGFA 相关的转化医学

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0 项与 HGFA 相关的专利（医药）

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296

项与 HGFA 相关的文献（医药）

2024-10-01·Seminars in Thrombosis and Hemostasis

Factor XII Structure–Function Relationships

Review

作者: Srivastava, Priyanka ; Ivanov, Ivan ; Shamanaev, Aleksandr ; Gailani, David ; Litvak, Maxim ; He, Tracey Z. ; Sun, Mao-Fu ; Dickeson, S. Kent ; Kumar, Sunil

AbstractFactor XII (FXII), the zymogen of the protease FXIIa, contributes to pathologic processes such as bradykinin-dependent angioedema and thrombosis through its capacity to convert the homologs prekallikrein and factor XI to the proteases plasma kallikrein and factor XIa. FXII activation and FXIIa activity are enhanced when the protein binds to a surface. Here, we review recent work on the structure and enzymology of FXII with an emphasis on how they relate to pathology. FXII is a homolog of pro-hepatocyte growth factor activator (pro-HGFA). We prepared a panel of FXII molecules in which individual domains were replaced with corresponding pro-HGFA domains and tested them in FXII activation and activity assays. When in fluid phase (not surface bound), FXII and prekallikrein undergo reciprocal activation. The FXII heavy chain restricts reciprocal activation, setting limits on the rate of this process. Pro-HGFA replacements for the FXII fibronectin type 2 or kringle domains markedly accelerate reciprocal activation, indicating disruption of the normal regulatory function of the heavy chain. Surface binding also enhances FXII activation and activity. This effect is lost if the FXII first epidermal growth factor (EGF1) domain is replaced with pro-HGFA EGF1. These results suggest that FXII circulates in blood in a “closed” form that is resistant to activation. Intramolecular interactions involving the fibronectin type 2 and kringle domains maintain the closed form. FXII binding to a surface through the EGF1 domain disrupts these interactions, resulting in an open conformation that facilitates FXII activation. These observations have implications for understanding FXII contributions to diseases such as hereditary angioedema and surface-triggered thrombosis, and for developing treatments for thrombo-inflammatory disorders.

2024-08-31·Experimental Neurobiology

Generation of Astrocyte-specific BEST1 Conditional Knockout Mouse with Reduced Tonic GABA Inhibition in the Brain

Article

作者: Choi, Sun Yeong ; Lee, C. Justin ; Lim, Jiwoon ; Koh, Wuhyun ; Kim, Ki Jung ; Joo, Jinhyeong

Bestrophin-1 (BEST1) is a Ca²⁺-activated anion channel known for its role in astrocytes. Best1 is permeable to gliotransmitters, including GABA, to contribute to tonic GABA inhibition and modulate synaptic transmission in neighboring neurons. Despite the crucial functions of astrocytic BEST1, there is an absence of genetically engineered cell-type specific conditional mouse models addressing these roles. In this study, we developed an astrocyte-specific BEST1 conditional knock-out (BEST1 aKO) mouse line. Using the embryonic stem cell (ES cell) targeting method, we developed Best1 floxed mice (C57BL/6JCya-Best1^em1flox/Cya), which have exon 3, 4, 5, and 6 of Best1 flanked by two loxP sites. By crossing with hGFAP-CreER^T2 mice, we generated Best1 floxed/hGFAP-CreER^T2 mice, which allowed for the tamoxifen-inducible deletion of Best1 under the human GFAP promoter. We characterized its features across various brain regions, including the striatum, hippocampal dentate gyrus (HpDG), and Parafascicular thalamic nucleus (Pf). Compared to the Cre-negative control, we observed significantly reduced BEST1 protein expression in immunohistochemistry (IHC) and tonic GABA inhibition in patch clamp recordings. The reduction in tonic GABA inhibition was 66.7% in the striatum, 46.4% in the HpDG, and 49.6% in the Pf. Our findings demonstrate that the BEST1 channel in astrocytes significantly contributes to tonic inhibition in the local brain areas. These mice will be valuable for future studies not only on tonic GABA release but also on tonic release of gliotransmitters mediated by astrocytic BEST1.

2024-08-01·Protein Science

Use of protease substrate specificity screening in the rational design of selective protease inhibitors with unnatural amino acids: Application to HGFA, matriptase, and hepsin

Article

作者: Damalanka, Vishnu C. ; Helander, Jonathan ; Poreba, Marcin ; Janetka, James W. ; Drag, Marcin ; De Bona, Paolo ; Kasperkiewicz, Paulina ; Lovell, Scott ; O'Donoghue, Anthony J. ; Kashipathy, Maithri M. ; Kooner, Anoopjit S. ; Mahoney, Matthew W. ; Battaile, Kevin P. ; Craik, Charles S. ; Rut, Wioletta ; Norman, Mariah

AbstractInhibition of the proteolytic processing of hepatocyte growth factor (HGF) and macrophage stimulating protein (MSP) is an attractive approach for the drug discovery of novel anticancer therapeutics which prevent tumor progression and metastasis. Here, we utilized an improved and expanded version of positional scanning of substrate combinatorial libraries (PS‐SCL) technique called HyCoSuL to optimize peptidomimetic inhibitors of the HGF/MSP activating serine proteases, HGFA, matriptase, and hepsin. These inhibitors have an electrophilic ketone serine trapping warhead and thus form a reversible covalent bond to the protease. We demonstrate that by varying the P2, P3, and P4 positions of the inhibitor with unnatural amino acids based on the protease substrate preferences learned from HyCoSuL, we can predictably modify the potency and selectivity of the inhibitor. We identified the tetrapeptide JH‐1144 (8) as a single digit nM inhibitor of HGFA, matriptase and hepsin with excellent selectivity over Factor Xa and thrombin. These unnatural peptides have increased metabolic stability relative to natural peptides of similar structure. The tripeptide inhibitor PK‐1‐89 (2) has excellent pharmacokinetics in mice with good compound exposure out to 24 h. In addition, we obtained an X‐ray structure of the inhibitor MM1132 (15) bound to matriptase revealing an interesting binding conformation useful for future inhibitor design.