更新于：2024-11-01

PEPD x XPNPEP1

更新于：2024-11-01

基本信息

关联

项与 PEPD x XPNPEP1 相关的药物

CQ31

靶点

PEPD x XPNPEP1

作用机制

PEPD抑制剂 [+1]

在研机构

Memorial Sloan Kettering Cancer Center

原研机构

Memorial Sloan Kettering Cancer Center

在研适应症

炎症

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

CQ80

靶点

PEPD x XPNPEP1

作用机制

PEPD抑制剂 [+1]

在研机构

Memorial Sloan Kettering Cancer Center

原研机构

Memorial Sloan Kettering Cancer Center

在研适应症-

非在研适应症-

最高研发阶段药物发现

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 PEPD x XPNPEP1 相关的临床结果

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100 项与 PEPD x XPNPEP1 相关的转化医学

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0 项与 PEPD x XPNPEP1 相关的专利（医药）

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项与 PEPD x XPNPEP1 相关的文献（医药）

2023-02-23·Journal of Medicinal Chemistry1区 · 医学

Optimized M24B Aminopeptidase Inhibitors for CARD8 Inflammasome Activation

1区 · 医学

Article

作者: Orth-He, Elizabeth L. ; Chen, Qifeng ; Bachovchin, Daniel A. ; Ball, Daniel P. ; Wang, Alvin ; Covelli, Dominic J. ; Bhattacharjee, Abir ; Rao, Sahana D. ; Huang, Hsin-Che ; Wang, Qinghui ; Hsiao, Jeffrey C.

Inflammasomes are innate immune signaling platforms that trigger pyroptotic cell death. NLRP1 and CARD8 are related human inflammasomes that detect similar danger signals, but NLRP1 has a higher activation threshold and triggers a more inflammatory form of pyroptosis. Both sense the accumulation of intracellular peptides with Xaa-Pro N-termini, but Xaa-Pro peptides on their own without a second danger signal only activate the CARD8 inflammasome. We recently reported that a dual inhibitor of the Xaa-Pro-cleaving M24B aminopeptidases PEPD and XPNPEP1 called CQ31 selectively activates the CARD8 inflammasome by inducing the build-up of Xaa-Pro peptides. Here, we performed structure-activity relationship studies on CQ31 to develop the optimized dual PEPD/XPNPEP1 inhibitor CQ80 that more effectively induces CARD8 inflammasome activation. We anticipate that CQ80 will become a valuable tool to study the basic biology and therapeutic potential of selective CARD8 inflammasome activation.

2020-06-01·Protein Expression and Purification4区 · 生物学

Engineering Xaa-Pro dipeptidyl aminopeptidase for specific cleavage of glucagon and glucagon-like peptide 1 from fusion proteins

4区 · 生物学

Article

作者: Thøgersen, Henning ; Vernet, Erik ; Shaw, Allan Christian ; Pedersen, Marie Østergaard

N-terminal extensions ("tags") have proven valuable for producing peptides using high throughput recombinant expression technologies. However, the applicability is hampered by the limited options for specific and efficient proteases to release the fully native sequence without additional amino acids in the N-terminal. Here we describe the Escherichia coli (E. coli) expression, purification and characterization of engineered variants of Xaa-Pro dipeptidyl aminopeptidase (Xaa-Pro-DAP) derived from Lactococcus lactis for cleavage of Gly-Pro dipeptide extension in the N-terminal of glucagon and glucagon-like peptide 1 (GLP-1(7-37)). By single amino acid substitution in the Xaa-Pro-DAP protease, significantly higher product yields were achieved. The combination of HRV14 3C protease and engineered Xaa-Pro-DAP is suggested for obtaining native N-terminal of peptides.

2018-08-01·Molecular Biotechnology4区 · 医学

Trichomonas vaginalis metalloproteinase TvMP50 is a monomeric Aminopeptidase P-like enzyme

4区 · 医学

Article

作者: Villalpando, José Luis ; Alvarez-Sánchez, María Elizbeth ; Morales-Montor, Jorge ; Puente-Rivera, Jonathan ; Arreola, Rodrigo ; Rudiño-Piñera, Enrique

Previously, metalloproteinase was isolated and identified from Trichomonas vaginalis, belonging to the aminopeptidase P-like metalloproteinase subfamily A/B, family M24 of clan MG, named TvMP50. The native and recombinant TvMP50 showed proteolytic activity, determined by gelatin zymogram, and a 50 kDa band, suggesting that TvMP50 is a monomeric active enzyme. This was an unexpected finding since other Xaa-Pro aminopeptidases/prolidases are active as a biological unit formed by dimers/tetramers. In this study, the evolutionary history of TvMP50 and the preliminary crystal structure of the recombinant enzyme determined at 3.4 Å resolution is reported. TvMP50 was shown to be a type of putative, eukaryotic, monomeric aminopeptidase P, and the crystallographic coordinates showed a monomer on a "pseudo-homodimer" array on the asymmetric unit that resembles the quaternary structure of the M24B dimeric family and suggests a homodimeric aminopeptidase P-like enzyme as a likely ancestor. Interestingly, TvMP50 had a modified N-terminal region compared with other Xaa-Pro aminopeptidases/prolidases with three-dimensional structures; however, the formation of the standard dimer is structurally unstable in aqueous solution, and a comparably reduced number of hydrogen bridges and lack of saline bridges were found between subunits A/B, which could explain why TvMP50 portrays monomeric functionality. Additionally, we found that the Parabasalia group contains two protein lineages with a "pita bread" fold; the ancestral monomeric group 1 was probably derived from an ancestral dimeric aminopeptidase P-type enzyme, and group 2 has a probable dimeric kind of ancestral eukaryotic prolidase lineage. The implications of such hypotheses are also presented.