Proteases as drug targets

2003 ◽  
Vol 70 ◽  
pp. 147-161 ◽  
Author(s):  
Andy J. Docherty ◽  
Tom Crabbe ◽  
James P. O'Connell ◽  
Colin R. Groom
Keyword(s):  
Rheumatoid Arthritis ◽  
Drug Targets ◽  
Enzyme Inhibitors ◽  
Proteolytic Enzymes ◽  
Angiotensin Converting Enzyme Inhibitors ◽  
Hiv Protease ◽  
Hiv Protease Inhibitors ◽  
Converting Enzyme Inhibitors ◽  
Recent Success ◽  
The Impact

The effective management of AIDS with HIV protease inhibitors, or the use of angiotensin-converting enzyme inhibitors to treat hypertension, indicates that proteases do make good drug targets. On the other hand, matrix metalloproteinase (MMP) inhibitors from several companies have failed in both cancer and rheumatoid arthritis clinical trials. Mindful of the MMP inhibitor experience, this chapter explores how tractable proteases are as drug targets from a chemistry perspective. It examines the recent success of other classes of drug for the treatment of rheumatoid arthritis, and highlights the need to consider where putative targets lie on pathophysiological pathways--regardless of what kind of therapeutic entity would be required to target them. With genome research yielding many possible new drug targets, it explores the likelihood of discovering proteolytic enzymes that are causally responsible for disease processes and that might therefore make better targets, especially if they lead to the development of drugs that can be administered orally. It also considers the impact that biologics are having on drug discovery, and in particular whether biologically derived therapeutics such as antibodies are likely to significantly alter the way we view proteases as targets and the methods used to discover therapeutic inhibitors.

scholarly journals Pandemic Perspective: Commonalities Between COVID-19 and Cardio-Oncology

2020 ◽  
Vol 7 ◽  
Author(s):  
Sherry-Ann Brown ◽  
Svetlana Zaharova ◽  
Peter Mason ◽  
Jonathan Thompson ◽  
Bicky Thapa ◽  
...  
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Enzyme Inhibitors ◽  
Angiotensin Receptor Blockers ◽  
Management Strategies ◽  
Angiotensin Converting Enzyme Inhibitors ◽  
Cancer Therapies ◽  
Converting Enzyme ◽  
Cytokine Release ◽  
Converting Enzyme Inhibitors ◽  
The Impact

Overlapping commonalities between coronavirus disease of 2019 (COVID-19) and cardio-oncology regarding cardiovascular toxicities (CVT), pathophysiology, and pharmacology are special topics emerging during the pandemic. In this perspective, we consider an array of CVT common to both COVID-19 and cardio-oncology, including cardiomyopathy, ischemia, conduction abnormalities, myopericarditis, and right ventricular (RV) failure. We also emphasize the higher risk of severe COVID-19 illness in patients with cardiovascular disease (CVD) or its risk factors or cancer. We explore commonalities in the underlying pathophysiology observed in COVID-19 and cardio-oncology, including inflammation, cytokine release, the renin-angiotensin-aldosterone-system, coagulopathy, microthrombosis, and endothelial dysfunction. In addition, we examine common pharmacologic management strategies that have been elucidated for CVT from COVID-19 and various cancer therapies. The use of corticosteroids, as well as antibodies and inhibitors of various molecules mediating inflammation and cytokine release syndrome, are discussed. The impact of angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) is also addressed, since these drugs are used in cardio-oncology and have received considerable attention during the COVID-19 pandemic, since the culprit virus enters human cells via the angiotensin converting enzyme 2 (ACE2) receptor. There are therefore several areas of overlap, similarity, and interaction in the toxicity, pathophysiology, and pharmacology profiles in COVID-19 and cardio-oncology syndromes. Learning more about either will likely provide some level of insight into both. We discuss each of these topics in this viewpoint, as well as what we foresee as evolving future directions to consider in cardio-oncology during the pandemic and beyond. Finally, we highlight commonalities in health disparities in COVID-19 and cardio-oncology and encourage continued development and implementation of innovative solutions to improve equity in health and healing.

scholarly journals The impact of ramipril on kidney function parameters in the chronic kidney disease patient with hypertension

2020 ◽  
Vol 11 (4) ◽  
pp. 6932-6937
Author(s):  
Mohammed Salim KT ◽  
Saravanakumar RT ◽  
Dilip C ◽  
Amrutha KP
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Kidney Function ◽  
Enzyme Inhibitors ◽  
Disease Patient ◽  
Cost Effective ◽  
Angiotensin Converting Enzyme Inhibitors ◽  
Converting Enzyme Inhibitors ◽  
Cost Effective Technique ◽  
The Impact

The administration of angiotensin converting enzyme inhibitors had gain popularity owing to their efficacy and safety in chronic kidney disease (CKD) patients. However, it is certainly necessary to look into the impact of the ramipril in kidney impaired individuals. We had enrolled 190 CKD with hypertensive patients based on the exclusion and inclusion criteria. The elder patients constituted to have a major share in the CKD population on ramipril therapy. From the study, it was found that the high costly brand was chosen the most and least cost was preferred only for 2 patients. The glomerular filtration rate (GFR) and serum creatinine, the major determinants of kidney function, had a small relationship with the dose of ramipril. However, the antihypertensive drug showed to have a favorable impact on patients overall treatment outcome. It is vital to evaluate the amount of protein in urine in case of a CKD patient. The easiest and cost effective technique, the dipstick urine protein test was done. The test value was found to be 1+ (30mg/dl) for majority of the patients and only 2 patients were observed with more than 1000 mg/dl. The ability of ramipril to reduce the progression of CKD can be attributed to the pooling of the data in +1 (30mg/dl) range.

scholarly journals The impact of angiotensin-converting-enzyme inhibitors versus angiotensin receptor blockers on 3-year clinical outcomes in patients with acute myocardial infarction without hypertension

PLoS ONE ◽  
2020 ◽  
Vol 15 (11) ◽  
pp. e0242314
Author(s):  
Ae-Young Her ◽  
Byoung Geol Choi ◽  
Seung-Woon Rha ◽  
Yong Hoon Kim ◽  
Cheol Ung Choi ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Enzyme Inhibitors ◽  
Angiotensin Converting Enzyme Inhibitors ◽  
Converting Enzyme ◽  
Converting Enzyme Inhibitors ◽  
Repeat Revascularization ◽  
History Of ◽  
Receptor Blockers ◽  
The Impact

This study aimed to investigate the impact of angiotensin-converting-enzyme inhibitors (ACEI) and angiotensin II type 1 receptor blockers (ARB) on 3-year clinical outcomes in acute myocardial infarction (AMI) patients without a history of hypertension who underwent successful percutaneous coronary intervention (PCI) with drug-eluting stents (DES). A total of 13,104 AMI patients who were registered in the Korea AMI registry (KAMIR)-National Institutes of Health (NIH) were included in the study. The primary endpoint was 3-year major adverse cardiac events (MACE), which was defined as the composite of all-cause death, recurrent myocardial infarction (MI), and any repeat revascularization. To adjust baseline potential confounders, an inverse probability weighting (IPTW) analysis was performed. The patients were divided into two groups: the ACEI group, n = 4,053 patients and the ARB group, n = 4,107 patients. During the 3-year clinical follow-up, the cumulative incidences of MACE (hazard ratio [HR], 0.843; 95% confidence interval [CI], 0.740–0.960; p = 0.010), any repeat revascularization (HR, 0.856; 95% CI, 0.736–0.995; p = 0.044), stroke (HR, 0.613; 95% CI, 0.417–0.901; p = 0.013), and re-hospitalization due to heart failure (HF) (HR, 0.399; 95% CI, 0.294–0.541; p <0.001) in the ACEI group were significantly lower than in the ARB group. In Korean patients with AMI without a history of hypertension, the use of ACEI was significantly associated with reduced incidences of MACE, any repeat revascularization, stroke, and re-hospitalization due to HF than those with the use of ARB.

scholarly journals Hypertension and COVID-19: Ongoing Controversies

2021 ◽  
Vol 8 ◽  
Author(s):  
Marijana Tadic ◽  
Sahrai Saeed ◽  
Guido Grassi ◽  
Stefano Taddei ◽  
Giuseppe Mancia ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Enzyme Inhibitors ◽  
Angiotensin Converting Enzyme Inhibitors ◽  
Newly Diagnosed ◽  
Converting Enzyme Inhibitors ◽  
Meta Analyses ◽  
Kidney Liver ◽  
The Impact ◽  
The Relationship ◽  
Clinical Overview

Coronavirus disease 2019 (COVID-19) has become a worldwide pandemic responsible for millions of deaths around the world. Hypertension has been identified as one of the most common comorbidities and risk factors for severity and adverse outcome in these patients. Recent investigations have raised the question whether hypertension represents a predictor of outcome in COVID-19 patients independently of other common comorbidities such as diabetes, obesity, other cardiovascular diseases, chronic kidney, liver, and pulmonary diseases. However, the impact of chronic and newly diagnosed hypertension in COVID-19 patients has been insufficiently investigated. The same is true for the relationship between blood pressure levels and outcomes in COVID-19 patients. It seems that the long discussion about the impact of angiotensin-converting enzyme inhibitors (ACEI) and blockers of angiotensin I receptors (ARB) on severity and outcome in COVID-19 is approaching an end because the large number of original studies and meta-analyses discarded the initial findings about higher prevalence of ACEI/ARB use in patients with unfavorable outcomes. Nevertheless, there are many controversies in the relationship between hypertension and COVID-19. The aim of this review article is to provide a clinical overview of the currently available evidence regarding the predictive value of hypertension, the effect of blood pressure levels, the impact of previously known and newly diagnosed hypertension, and the effect of antihypertensive therapy on the severity and outcomes in COVID-19 patients.

Angiotensins and rheumatoid arthritis

2019 ◽  
Vol 56 (6) ◽  
pp. 753-759
Author(s):  
N. M. Savushkina ◽  
E. A. Galushko ◽  
N. V. Demidova ◽  
A. V. Gordeev
Keyword(s):  
Rheumatoid Arthritis ◽  
Enzyme Inhibitors ◽  
Renin Angiotensin System ◽  
Angiotensin Converting Enzyme Inhibitors ◽  
The Body ◽  
Converting Enzyme Inhibitors ◽  
In Vivo Experiments ◽  
Endothelial Growth Factor

At present, the role of the renin-angiotensin system (RAS) in regulating the cardiovascular system and maintaining water and electrolyte homeostasis has been well studied. However, over the past decades, new components of the RAS have been identified, suggesting a wider range of its potential effects on the body. It is of fundamentally importance for rheumatologists to affect inflammation, including rheumatoid inflammation, through blockade of angiotensin (AT) II formation via the effects of AT 1–7 and angiotensin-converting enzyme inhibitors, as well as through suppression of angiogenesis, primarily by reducing the production of endothelial growth factor. The organ-protective and antiinflammatory potential of drugs that reduce the production of AT, which has been proven in in vitro and in vivo experiments, allows us to consider them as first-line angiotropic agents in patients with rheumatoid arthritis, especially in the presence of concomitant hypertension and/or nephropathy.

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