Matrix metalloproteinases inhibitors in idiopathic pulmonary fibrosis: Medicinal chemistry perspectives

Yang, Lin; Shi, Yaojie; Su, Xingping; Ouyang, Liang; Wang, Guan; Ye, Tinghong

doi:10.1016/j.ejmech.2021.113714

Cited by 15 publications

(13 citation statements)

References 109 publications

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“…MMPs/TIMPs play an important role in 1). Although the pathological processes of MMPs and IPF have been verified, there are no MMP inhibitors for the treatment of IPF in the clinic (Yue et al, 2021). ECM contains a variety of signal molecules secreted by cells; therefore, the ECM is a transfer station for signal exchange.…”

Section: Ecm Regulatorsmentioning

confidence: 99%

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Research Progress in the Molecular Mechanisms, Therapeutic Targets, and Drug Development of Idiopathic Pulmonary Fibrosis

et al. 2022

Front. Pharmacol.

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Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease. Recent studies have identified the key role of crosstalk between dysregulated epithelial cells, mesenchymal, immune, and endothelial cells in IPF. In addition, genetic mutations and environmental factors (e.g., smoking) have also been associated with the development of IPF. With the recent development of sequencing technology, epigenetics, as an intermediate link between gene expression and environmental impacts, has also been reported to be implicated in pulmonary fibrosis. Although the etiology of IPF is unknown, many novel therapeutic targets and agents have emerged from clinical trials for IPF treatment in the past years, and the successful launch of pirfenidone and nintedanib has demonstrated the promising future of anti-IPF therapy. Therefore, we aimed to gain an in-depth understanding of the underlying molecular mechanisms and pathogenic factors of IPF, which would be helpful for the diagnosis of IPF, the development of anti-fibrotic drugs, and improving the prognosis of patients with IPF. In this study, we summarized the pathogenic mechanism, therapeutic targets and clinical trials from the perspective of multiple cell types, gene mutations, epigenetic and environmental factors.

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Section: Ecm Regulatorsmentioning

confidence: 99%

“…Many studies have focused on MMPs and explored their potential value in resisting IPF ( Table 1 ). Although the pathological processes of MMPs and IPF have been verified, there are no MMP inhibitors for the treatment of IPF in the clinic ( Yue et al, 2021 ).…”

Section: Important Cells and Extracellular Matrix Involved In The Pat...mentioning

confidence: 99%

Research Progress in the Molecular Mechanisms, Therapeutic Targets, and Drug Development of Idiopathic Pulmonary Fibrosis

et al. 2022

Front. Pharmacol.

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“…Muchos estudios se han centrado en las MMPs y han explorado su valor potencial en la resistencia a la FPI (Tabla 1). Aunque se ha verificado la participación de las MMPs en los procesos patológicos de la FPI, no se dispone de inhibidores de las MMPs para el tratamiento de la FPI en la clínica [93].…”

Section: Células Importantes Y Matriz Extracelular Implicadas En La P...unclassified

Avances en la investigación de los mecanismos moleculares, los blancos terapéuticos y el desarrollo de fármacos para la fibrosis pulmonar idiopática

et al. 2022

Kompass Neumol

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La fibrosis pulmonar idiopática (FPI) es una enfermedad pulmonar intersticial de carácter mortal. Estudios recientes han identificado el papel clave de la interacción entre las células epiteliales, mesenquimales, inmunitarias y endoteliales desreguladas en la FPI. Además, algunas mutaciones genéticas y ciertos factores ambientales (por ejemplo, el tabaquismo) se han asociado con el desarrollo de la FPI. Con el reciente desarrollo de la tecnología de secuenciación, también se ha señalado que la epigenética, como vínculo intermedio entre la expresión genética y los impactos ambientales, está implicada en la fibrosis pulmonar. Aunque se desconoce la etiología de la FPI, en los últimos años han surgido blancos y agentes terapéuticos novedosos para el tratamiento de la FPI, y el éxito del lanzamiento de la pirfenidona y el nintedanib ha demostrado que la terapia contra la FPI tiene un futuro prometedor. Por lo tanto, nuestro objetivo es conocer en profundidad los mecanismos moleculares subyacentes y los factores patogénicos de la FPI, lo que sería útil para el diagnóstico de la FPI, el desarrollo de fármacos antifibróticos y un mejor pronóstico para los pacientes con FPI. En este estudio resumimos el mecanismo patogénico, los blancos terapéuticos y los ensayos clínicos considerando múltiples tipos de células y mutaciones genéticas, así como factores epigenéticos y ambientales.

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“…Because of the obvious importance of MMPs in cancer-related processes, many MMP inhibitors have been designed over the past 40 years. Yet, to date, all of them have failed in clinical trials, probably due to their high toxicity, , their nonspecific metal binding (i.e., binding not only to zinc but also to the metals in metalloproteins other than MMPs), and poor solubility . Antibodies that have been raised against MMP-2/MMP-9 and against MMP-14 have shown therapeutic promise in preclinical models, but their development as therapeutics has been impeded by the well-known limitations associated with antibodies, including the high cost of their recombinant production in mammalian cells, their lack of amenability to site-specific incorporation of chemical modalities, and their potential undesired effector functions, together with considerable intellectual property barriers to their development …”

Section: Introductionmentioning

confidence: 99%

Bioorthogonal PEGylation Prolongs the Elimination Half-Life of N-TIMP2 While Retaining MMP Inhibition

et al. 2022

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Tissue inhibitors of metalloproteinases (TIMPs) are natural inhibitors of the matrix metalloproteinase (MMP) family of proteins, whose members are key regulators of the proteolysis of extracellular matrix components and hence of multiple biological processes. In particular, imbalanced activity of matrix metalloproteinase-14 (MMP-14) may lead to the development of cancer and cardiovascular and other diseases. This study aimed to engineer TIMP2, one of the four homologous TIMPs, as a potential therapeutic by virtue of its ability to bind to the active-site Zn 2+ of MMP-14. However, the susceptibility to degradation of TIMP2 and its small size, which results in a short circulation halflife, limit its use as a therapeutic. PEGylation was thus used to improve the pharmacokinetic profile of TIMP2. PEGylation of the MMP-targeting N-terminal domain of TIMP2 (N-TIMP2), via either cysteine or lysine residues, resulted in a significant decrease in N-TIMP2 affinity toward MMP-14 or multisite conjugation and conjugate heterogeneity, respectively. Our strategy designed to address this problem was based on incorporating a noncanonical amino acid (NCAA) into N-TIMP2 to enable site-specific mono-PEGylation. The first step was to incorporate the NCAA propargyl lysine (PrK) at position S31 in N-TIMP2, which does not interfere with the N-TIMP2−MMP-14 binding interface. Thereafter, site-specific PEGylation was achieved via a click chemistry reaction between N-TIMP2-S31PrK and PEG-azide-20K. Inhibition studies showed that PEGylated N-TIMP2-S31PrK did indeed retain its inhibitory activity toward MMP-14. The modified protein also showed improved serum stability vs non-PEGylated N-TIMP2. In vivo pharmacokinetic studies in mice revealed a significant 8-fold increase in the elimination half-life of PEGylated N-TIMP2 vs the non-PEGylated protein. This study shows that site-specific bioorthogonal mono-PEGylation extends the half-life of N-TIMP2 without impairing its biological activity, thereby highlighting the advantage of this strategy for generating potent PEGylated proteins.

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Matrix metalloproteinases inhibitors in idiopathic pulmonary fibrosis: Medicinal chemistry perspectives

Cited by 15 publications

References 109 publications

Research Progress in the Molecular Mechanisms, Therapeutic Targets, and Drug Development of Idiopathic Pulmonary Fibrosis

Research Progress in the Molecular Mechanisms, Therapeutic Targets, and Drug Development of Idiopathic Pulmonary Fibrosis

Avances en la investigación de los mecanismos moleculares, los blancos terapéuticos y el desarrollo de fármacos para la fibrosis pulmonar idiopática

Bioorthogonal PEGylation Prolongs the Elimination Half-Life of N-TIMP2 While Retaining MMP Inhibition

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