Leu-Leu-Pro(Leu-Leu-Pro) - 药物靶点：ACE_在研适应症：高血压_专利_临床

概要

基本信息

药物类型

合成多肽

别名

LLP

靶点

ACE

作用方式

抑制剂

作用机制

ACE抑制剂(血管紧张素转化酶抑制剂)

治疗领域

心血管疾病

在研适应症

高血压

非在研适应症-

原研机构

广西民族大学

在研机构

广西民族大学

非在研机构-

权益机构-

最高研发阶段临床前

首次获批日期-

最高研发阶段(中国)临床前

特殊审评-

关联

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100 项与 Leu-Leu-Pro 相关的专利（医药）

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54

项与 Leu-Leu-Pro 相关的文献（医药）

2025-09-01·BIOORGANIC CHEMISTRY

Structure-activity relationship and molecular interaction mechanisms of the ACE-inhibitory tripeptide LL-X

Article

作者: Ma, Zhengkun ; Lan, Xiongdiao ; Cai, Mengmeng ; Yang, Cuicui ; Liu, Pengru

Investigating the molecular interaction mechanisms of angiotensin-converting enzyme (ACE) inhibitory peptides is valuable in antihypertensive drug development. In this study, we designed two novel peptide variants, Leu-Leu-Phe (LLF) and Leu-Leu-Pro (LLP), by substituting the C-terminal tyrosine (Tyr) in casein-derived Leu-Leu-Tyr (LLY) with phenylalanine (Phe) and proline (Pro), respectively, to investigate the impact of C-terminal amino acid properties of peptide on ACE inhibition. The ACE inhibitory activity, inhibition kinetics, peptides-ACE binding mechanisms, and LLF and LLP conformational relationship were systematically investigated with comparative assessment against the LLY. The results showed the ACE inhibitory activity of the synthetic peptide (LLF: IC₅₀ = 168.57 ± 5.11 μM; LLP: IC₅₀ = 96.64 ± 2.93 μM) was significantly lower than that casein-derived tripeptide LLY (IC₅₀ = 44.16 ± 2.45 μM). The Lineweaver-Burk plots and molecular docking indicated that both LLF and LLP were noncompetitive inhibitors, which was consistent with LLY. Molecular dynamics simulations validated their stable binding to the ACE complex. The comparison of the three peptides interacting with ACE using multispectral techniques indicated that LLY resulted in the formation of a greater number of disordered protein structural regions, rendering it more active than the other peptides. Consequently, we concluded that the role of the C-terminal Tyr in the ACE inhibitory peptide LLY is more significant than that of Phe and Pro. This study highlights the crucial influence of C-terminal amino acids on the inhibitory activity of tripeptides, providing an essential theoretical foundation for the rational design of effective ACE inhibitory peptides.

2025-08-01·MOLECULAR IMMUNOLOGY

Gut microbiota-derived Proline-Leucine dipeptide aggravated sepsis-induced acute lung injury via activating Nod2/NF-κB signaling pathway

Article

作者: Zhuo, Yuzhen ; Wei, Ao ; Yang, Lei ; Wang, Xiangyu ; He, Siqi ; He, Liangyong ; Wang, Ximo ; Zhong, Chengliang ; Zhang, Sijia ; Cui, Lingzhi

OBJECTIVE:

Gut microbiota-derived metabolites can modulate lung tissue damage via the gut-lung axis. This study aimed to delineate the alterations in gut microbiota and metabolites associated with sepsis and elucidate their role in potentiating lung tissue damage.

METHODS:

We employed 16S rDNA sequencing and non-targeted metabolomics to assess the changes in gut microbiota and metabolites, utilizing a rat model of sepsis. Furthermore, we investigated the contributions of the gut microbiota-derived Proline-Leucine (Pro-Leu) dipeptide and lipopolysaccharide (LPS) in driving lung inflammation, utilizing both mouse models and MH-S cells.

RESULTS:

Our findings indicate that sepsis significantly diminished gut microbiota diversity and markedly increased the relative abundance of Bacteroidetes and Escherichia-Shigella, as well as the metabolite Pro-Leu. Notably, Pro-Leu levels correlated with changes in bacterial communities. Additionally, Pro-Leu effectively exacerbated sepsis-induced lung damage. Both Pro-Leu and LPS notably enhanced pro-inflammatory cytokine production (TNF-α, IL-6, and IL-1β) by up-regulating C/EBP-β, p-NF-κB, and NOD2 in lung tissues and MH-S cells.

CONCLUSIONS:

Our findings suggest that Pro-Leu and LPS can synergistically intensify lung inflammation by activating the C/EBP-β/NOD2/NF-κB signaling pathways.

IMPORTANCE:

Our findings indicate that sepsis can lead to a disruption of the gut microbiota, an increase in pathogenic bacteria such as Escherichia-Shigella and Bacteroides, and that metabolites derived from the gut microbiota can modulate the lung inflammatory response through the gut-lung axis. Notably, Pro-Leu, a metabolite produced by the gut microbiota, was found to aggravate sepsis-induced ALI by activating the C/EBP-β/NOD2/NF-κB signaling pathways.

2025-05-01·ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION

Geographic Variation in Prosthesis Prescription Disparities Between White and Black Veterans After Major Lower Limb Amputation: A Retrospective Cohort Analysis

Article

作者: Roberts, Anthony I ; Resnik, Linda J

OBJECTIVE:

To examine racial disparities in lower limb prosthesis (LLP) prescription practices between White and Black veterans across different geographic levels within the United States Veterans Health Administration (VHA) and explore how racial disparities in LLP prescription practices differ by amputation level.

DESIGN:

Retrospective cohort study.

SETTING:

VHA facilities across the United States.

PARTICIPANTS:

A total of 12,143 White and 4711 Black veterans who underwent major lower limb amputation between 2010 and 2022 in a VHA facility, including 4885 with transfemoral amputations (TFA) and 11,969 with transtibial amputations (TTA).

INTERVENTIONS:

Not applicable.

MAIN OUTCOME MEASURES:

Age-standardized percentage point (pp) differences in LLP prescriptions between White and Black veterans within 12 months post-amputation, analyzed at national, regional, and Veterans Integrated Service Network (VISN) levels. A positive pp difference indicates a racial disparity, meaning a higher proportion of White veterans were prescribed LLPs compared with Black veterans.

RESULTS:

Nationally, 54.5% of veterans received an LLP prescription within 12 months post-amputation, with the age-standardized pp difference in LLP prescriptions favoring White veterans by 5.06 pp (95% confidence limits [CLs], 2.51,7.61). Regional analysis revealed variations, with the Continental region showing the largest disparity (9.10 pp; 95% CLs: 4.48, 13.71) and the Pacific region the smallest (3.27 pp; 95% CLs: -3.87,10.42). The VISN-level analysis uncovered greater variations, ranging from -9.26 to 14.54 pp. Disparities were more pronounced for veterans with TFA (5.25 pp; 95% CLs: 1.91, 8.59) compared with TTA (4.52 pp; 95% CLs: 1.54, 7.50).

CONCLUSIONS:

Significant geographic variations exist in racial disparities for LLP prescriptions across the VHA, with most areas favoring White veterans. Disparities were more pronounced for veterans with transfemoral amputations, highlighting the need for targeted interventions to improve equity in access to prosthetic care, especially for veterans with more proximal amputations and in regions and VISNs with the largest disparities.

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