Structural bases for substrate and inhibitor recognition by matrix metaloproteinases

Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases which are involved in the proteolytic processing of several components of the extracellular matrix. As a consequence, MMPs are implicated in several physiological and pathological processes, like skeletal growth and remodelling, wound healing, cancer, arthritis, and multiple sclerosis, raising a very widespread interest toward this class of enzymes as potential therapeutic targets. Here, structure-function relationships are discussed to highlight the role of different MMP domains on substrate/inhibitor recognition and processing and to attempt the formulation of advanced guidelines, based on natural substrates, for the design of inhibitors more efficient in vivo. © 2008 Bentham Science Publishers Ltd

Unspoken inequality: How COVID-19 has exacerbated existing vulnerabilities of asylum-seekers, refugees, and undocumented migrants in South Africa

An estimated 2 million foreign-born migrants of working age (15-64) were living in South Africa (SA) in 2017. Structural and practical xenophobia has driven asylum-seekers, refugees, and undocumented migrants in SA to abject poverty and misery. The Coronavirus Disease 2019 (COVID-19) containment measures adopted by the SA government through the lockdown of the nation have tremendously deepened the unequal treatment of asylum-seekers and refugees in SA. This can be seen through the South African government's lack of consideration of this marginalized population in economic, poverty, and hunger alleviation schemes. Leaving this category of our society out of the national response safety nets may lead to negative coping strategies causing mental health issues and secondary health concerns. An effective response to the socioeconomic challenges imposed by the COVID-19 pandemic should consider the economic and health impact of the pandemic on asylum-seekers, refugees, and undocumented migrants

In silico scaffold evaluation and solid phase approach to identify new gelatinase inhibitors

Among matrix metalloproteinases (MMPs), gelatinases MMP-2 (gelatinase A) and MMP-9 (gelatinase B) play a key role in a number of physiological processes such as tissue repair and fibrosis. Many evidences point out their involvement in a series of pathological events, such as arthritis, multiple sclerosis, cardiovascular diseases, inflammatory processes and tumor progression by degradation of the extracellular matrix. To date, the identification of non-specific MMP inhibitors has made difficult the selective targeting of gelatinases. In this work we report the identification, design and synthesis of new gelatinase inhibitors with appropriate drug-like properties and good profile in terms of affinity and selectivity. By a detailed in silico protocol and innovative and versatile solid phase approaches, a series of 4-thiazolydinyl- N-hydroxycarboxyamide derivatives were identified. In particular, compounds 9a and 10a showed a potent inhibitory activity against gelatinase B and good selectivity over the other MMP considered in this study. The identified compounds could represent novel potential candidates as therapeutic agents

In silico scaffold evaluation and solid phase approach to identify new gelatinase inhibitors

Among matrix metalloproteinases (MMPs), gelatinases MMP-2 (gelatinase A) and MMP-9 (gelatinase B) play a key role in a number of physiological processes such as tissue repair and fibrosis. Many evidences point out their involvement in a series of pathological events, such as arthritis, multiple sclerosis, cardiovascular diseases, inflammatory processes and tumor progression by degradation of the extracellular matrix. To date, the identification of non-specific MMP inhibitors has made difficult the selective targeting of gelatinases. In this work we report the identification, design and synthesis of new gelatinase inhibitors with appropriate drug-like properties and good profile in terms of affinity and selectivity. By a detailed in silico protocol and innovative and versatile solid phase approaches, a series of 4-thiazolydinyl- N-hydroxycarboxyamide derivatives were identified. In particular, compounds 9a and 10a showed a potent inhibitory activity against gelatinase B and good selectivity over the other MMP considered in this study. The identified compounds could represent novel potential candidates as therapeutic agents

Synthesis and biochemical evaluation of (R)-5-acyloxymethyl- and (S)-5-acylaminomethyl-3-(1H-pyrrol-1-yl)-2-oxazolidinones as new anti-monoamine oxidase (anti-MAO) agents.

(R)-5-Acyloxymethyl- and (S)-5-acylaminomethyl-3-(1H-pyrrol-1-yl)-2-oxazolidinones 2a-s were synthesized as pyrrole analogues of toloxatone (Humoryl(R)), an anti-MAO agent used in clinical therapy because of its antidepressant properties. Their ability to inhibit the enzymatic isoforms MAO-A and MAO-B was evaluated. From the data most 2a-s showed high reversibility and selective MAO-A inhibitory activity. They exhibited an inhibitory potency (KiMAO-A) of 0.16-0.90 muM comparable to that found for toloxatone (KiMAO-A = 0.38 muM), the A isoform being 11-fold more selective. The results indicate that 2a-s show promise as new antidepressant agents