Abstract
Transthyretin is a homotetrameric protein that carries thyroxine and retinol binding protein in plasma and is associated with a variety of amyloid diseases. One approach to the potential treatment of TTR amyloidosis is the stabilization of the native tetramer, over the dissociative transition state, through the binding of small molecules; this increases the kinetic barrier for tetramer dissociation and prevents protein misfolding. Several molecules discovered through focused screening, or created utilizing the structure-based design, were studied to identify the structural features that could make up for a good candidate drug. In this review, we examine several different chemical classes of TTR fibril formation inhibitors, highlighting the structural modifications that have led to an improvement or to a decrease of their potency and/or selectivity.
Keywords: Transthyretin (TTR), TTR-amyloidosis, familial transthyretin amyloidosis (FAP, FAC, SSA), protein-misfolding disorders, TTR amyloid fibril formation inhibitors, structure based drug discovery, amyloid fibril formation inhibitors, SAR
Current Medicinal Chemistry
Title:TTR Fibril Formation Inhibitors: Is there a SAR?
Volume: 19 Issue: 15
Author(s): S. Nencetti, E. Orlandini
Affiliation:
Keywords: Transthyretin (TTR), TTR-amyloidosis, familial transthyretin amyloidosis (FAP, FAC, SSA), protein-misfolding disorders, TTR amyloid fibril formation inhibitors, structure based drug discovery, amyloid fibril formation inhibitors, SAR
Abstract: Transthyretin is a homotetrameric protein that carries thyroxine and retinol binding protein in plasma and is associated with a variety of amyloid diseases. One approach to the potential treatment of TTR amyloidosis is the stabilization of the native tetramer, over the dissociative transition state, through the binding of small molecules; this increases the kinetic barrier for tetramer dissociation and prevents protein misfolding. Several molecules discovered through focused screening, or created utilizing the structure-based design, were studied to identify the structural features that could make up for a good candidate drug. In this review, we examine several different chemical classes of TTR fibril formation inhibitors, highlighting the structural modifications that have led to an improvement or to a decrease of their potency and/or selectivity.
Export Options
About this article
Cite this article as:
S. Nencetti, E. Orlandini , TTR Fibril Formation Inhibitors: Is there a SAR?, Current Medicinal Chemistry 2012; 19 (15) . https://dx.doi.org/10.2174/092986712800269326
DOI https://dx.doi.org/10.2174/092986712800269326 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
Call for Papers in Thematic Issues
Advances in Medicinal Chemistry: From Cancer to Chronic Diseases.
The broad spectrum of the issue will provide a comprehensive overview of emerging trends, novel therapeutic interventions, and translational insights that impact modern medicine. The primary focus will be diseases of global concern, including cancer, chronic pain, metabolic disorders, and autoimmune conditions, providing a broad overview of the advancements in ...read more
Cellular and Molecular Mechanisms of Non-Infectious Inflammatory Diseases: Focus on Clinical Implications
The Special Issue covers the results of the studies on cellular and molecular mechanisms of non-infectious inflammatory diseases, in particular, autoimmune rheumatic diseases, atherosclerotic cardiovascular disease and other age-related disorders such as type II diabetes, cancer, neurodegenerative disorders, etc. Review and research articles as well as methodology papers that summarize ...read more
Chalcogen-modified nucleic acid analogues
Chalcogen-modified nucleosides, nucleotides and oligonucleotides have been of great interest to scientific research for many years. The replacement of oxygen in the nucleobase, sugar or phosphate backbone by chalcogen atoms (sulfur, selenium, tellurium) gives these biomolecules unique properties resulting from their altered physical and chemical properties. The continuing interest in ...read more
Current advances in inherited cardiomyopathy
Describe in detail all novel advances in multimodality imaging related to inherited cardiomyopathy diagnosis and prognosis. Shed light to deeper phenotypic characterization. Acknowledge recent advances in genetics, genomics and precision medicineread more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
The Role of Chymase in Vascular Remodeling and Tissue Fibrosis
Current Hypertension Reviews Susceptibility Risk Alleles of -238G/A, -308G/A and -1031T/C Promoter Polymorphisms of TNF-α Gene to Uterine Leiomyomas
Recent Advances in DNA & Gene Sequences (Discontinued) Sirtuins: Novel Players in Male Reproductive Health
Current Medicinal Chemistry The Progress Towards the Development of DHQO Derivatives and Related Analogues with Inotropic Effects
Mini-Reviews in Medicinal Chemistry Roles of miRNA in Cardiovascular Development and Dysfunction
Current Medicinal Chemistry Cardiovascular Disease Risk Among the Poor and Homeless – What We Know So Far
Current Cardiology Reviews Target-based Anti-angiogenic Therapy in Breast Cancer
Current Pharmaceutical Design FoxO3a Governs Early Microglial Proliferation and Employs Mitochondrial Depolarization with Caspase 3, 8, and 9 Cleavage During Oxidant Induced Apoptosis
Current Neurovascular Research Hypertension in Patients with Severe Aortic Stenosis: Emphasis on Antihypertensive Treatment and the Risk of Syncope
Current Hypertension Reviews Inhibitory Effect of PD-1/PD-L1 and Blockade Immunotherapy in Leukemia
Combinatorial Chemistry & High Throughput Screening The Chemical Design and Synthesis of Linkers Used in Antibody Drug Conjugates
Current Topics in Medicinal Chemistry The Failing Heart in Pediatric Dilated Cardiomyopathy Caused by Excessive Water Drinking: A Case Report and Brief Review
New Emirates Medical Journal PET Imaging of Beta-Adrenoceptors in Human Brain: A Realistic Goal or a Mirage?
Current Pharmaceutical Design The Impact of Hypertension as a Road to Heart Failure with Preserved Ejection Fraction: Diagnostic Value of Two-Dimensional Speckle Tracking Echocardiography for the Early Impairment of Left Atrial-Left Ventricular-Arterial Coupling
Current Hypertension Reviews Cardiovascular Effects of Neuregulin-1/ErbB Signaling: Role in Vascular Signaling and Angiogenesis
Current Pharmaceutical Design HIV-1 Infection In Children: A Clinical and Immunologic Overview
Current HIV Research Multiple Sclerosis: Pathogenesis and Treatment
Current Neuropharmacology The Meaning of Different Forms of Structural Myocardial Injury, Immune Response and Timing of Infarct Necrosis and Cardiac Repair
Current Vascular Pharmacology Erythropoietin in Stroke Therapy: Friend or Foe
Current Medicinal Chemistry Ionophores as Potent Anti-malarials: A Miracle in the Making
Current Topics in Medicinal Chemistry