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Current Medicinal Chemistry 2012Transthyretin is an amyloidogenic protein associated with several amyloidosis, namely familial amyloidotic polyneuropathy, familial amyloidotic cardiomyopathy, and... (Review)
Review
Transthyretin is an amyloidogenic protein associated with several amyloidosis, namely familial amyloidotic polyneuropathy, familial amyloidotic cardiomyopathy, and central nervous system selective amyloidosis, familial rare diseases caused by single point mutants, and senile systemic amyloidosis associated with wild-type TTR. The current model for amyloid fibril formation involves initial dissociation of the native TTR tetramer into non-native monomers which associate into soluble oligomers and protofibrils that evolve to mature amyloid deposits. A number of efforts are addressed to identify small molecules targeting the formation, clearance, or assembly of toxic aggregates as a promising therapeutic strategy to treat amyloidosis. This review classifies and summarizes the different strategies and assays that have been developed in vitro, ex vivo, and in vivo as tools to screen libraries of compounds or to test compounds from rational design in the search of drug candidates for the treatment of TTR-associated amyloidosis. Depending on the property they measure, the assays are classified as: a) in vitro assays that monitor protein aggregation and/or fibril formation, b) in vitro assays that monitor binding to native protein, c) ex vivo TTR plasma selectivity assays, d) in vitro assays for tetrameric TTR stabilization, e) cellular assays, and f) animal models to evaluate amyloidosis inhibitors.
Topics: Amyloid; Amyloidosis; Animals; Disease Models, Animal; Drug Evaluation, Preclinical; Humans; Ligands; Mice; Prealbumin
PubMed: 22471983
DOI: 10.2174/092986712800269281 -
The International Journal of... Apr 2017The cytotoxicity of amyloidogenic proteins such as transthyretin (TTR) has implications for neurodegeneration and other pathologies, but is not well understood. In the...
The cytotoxicity of amyloidogenic proteins such as transthyretin (TTR) has implications for neurodegeneration and other pathologies, but is not well understood. In the current study, potential effects of misfolded, aggregated TTRs (agTTR) upon a major cell membrane function-endocytosis-were assessed. Internalization of transferrin (Tf), a ligand whose receptor-mediated endocytosis is well characterized, was analyzed in different cell types after treatment with agTTR. The results indicate disruption of Tf endocytosis: 20-25% inhibition by agTTR relative to the same concentrations of normal soluble TTR, or relative to another control protein, albumin (p<0.05 for agTTR relative to controls). No statistically significant difference was observed for cell surface Tf binding between agTTR-treated and control cells. This is the first evidence for endocytic disruption by agTTR, and presents a novel cytotoxicity mechanism that may account for previously reported inhibitory effects of amyloidogenic TTR on neuronal growth.
Topics: Animals; Biological Assay; Biological Transport; Cell Line, Tumor; Colorimetry; Endocytosis; Humans; Mice; Prealbumin; Protein Binding
PubMed: 28189844
DOI: 10.1016/j.biocel.2017.02.002 -
The Journal of Biological Chemistry May 1985The primary structures of rabbit and rat prealbumin have been determined. The amino acid sequence of rabbit prealbumin was determined by analyses of peptides obtained by... (Comparative Study)
Comparative Study
The primary structures of rabbit and rat prealbumin have been determined. The amino acid sequence of rabbit prealbumin was determined by analyses of peptides obtained by trypsin and Staphylococcus aureus protease digestions. The rat prealbumin sequence was deduced by analyses of tryptic peptides as well as by nucleotide sequencing of cDNA clones. Both amino acid sequences contain 127 amino acid residues, the same as human prealbumin. Pairwise comparisons show that the three sequences are more than 80% identical. All three prealbumins were found to display significant sequence homology with human thyroxine-binding globulin. A comparison of the primary structures of the prealbumins with the tertiary structure of human prealbumin shows that amino acid replacements are preferentially located at the surface of the molecule and in the loops connecting the beta-strands. The locations of the replacements are discussed as regards the different molecular interactions in which prealbumin is involved.
Topics: Amino Acid Sequence; Animals; Binding Sites; DNA; Humans; Prealbumin; Protein Conformation; Rabbits; Rats; Retinol-Binding Proteins; Species Specificity; Thyroxine-Binding Proteins
PubMed: 3922975
DOI: No ID Found -
Current Pharmaceutical Design 2008Transthyretin (TTR) is a homotetrameric serum and cerebrospinal fluid protein that transports both thyroxine (T(4)) and the retinol-retinol binding protein complex... (Review)
Review
Transthyretin (TTR) is a homotetrameric serum and cerebrospinal fluid protein that transports both thyroxine (T(4)) and the retinol-retinol binding protein complex (holoRBP). Rate-limiting tetramer dissociation and rapid monomer misfolding and misassembly of variant TTR results in familial amyloid polyneuropathy (FAP), familial amyloid cardiomyopathy (FAC), or familial central nervous system amyloidosis. Analogous misfolding of wild-type TTR results in senile systemic amyloidosis (SSA) characterized by sporadic amyloidosis in elderly populations. With the availability of genetic and immunohistochemical diagnostic tests, patients with TTR amyloidosis have been found in many nations worldwide. Recent studies indicate that TTR amyloidosis is not a rare endemic disease as previously thought. The only effective treatment for the familial TTR amyloidoses is liver transplantation; however, this strategy has a number of limitations, including a shortage of donors, a requirement for surgery for both the recipient and living donor, and the high cost. Furthermore, a large number of patients are not good transplant candidates. Recent studies focused on the TTR gene and protein have provided insight into the pathogenesis of TTR amyloidosis and suggested new strategies for therapeutic intervention. TTR tetramer (native state) kinetic stabilization by small molecule binding, immune therapy, and gene therapy with small interfering RNAs, antisense oligonucleotides, and single-stranded oligonucleotides are promising strategies based on our understanding of the pathogenesis of TTR amyloidosis. Among these, native state kinetic stabilization by diflunisal and Fx-1006A, a novel therapeutic strategy against protein misfolding diseases, are currently in Phase II/III clinical trials.
Topics: Amyloidosis; Animals; Clinical Trials as Topic; Genetic Therapy; Humans; Immunotherapy; Liver Transplantation; Prealbumin; Protein Binding; Protein Folding; Protein Stability; Small Molecule Libraries
PubMed: 19075702
DOI: 10.2174/138161208786404155 -
Journal of Structural Biology Jun 2000Transthyretin amyloidosis represents a spectrum of clinical syndromes that, in all cases except senile systemic amyloidosis, are dependent on the mutation present in the... (Review)
Review
Transthyretin amyloidosis represents a spectrum of clinical syndromes that, in all cases except senile systemic amyloidosis, are dependent on the mutation present in the transthyretin (TTR) protein. Although the role of amyloid deposits in the pathogenesis of the disease is not clear, preventing their formation or promoting their disaggregation is necessary to control the development of clinical symptoms. The design of therapies aiming at preventing amyloid formation or promoting its dissociation requires detailed knowledge of the fibrils' molecular structure and a complete view about the factors responsible for protein aggregation. This review is focused on the structural studies, performed on amyloid fibrils and amyloidogenic TTR variants, aiming at understanding the aggregation mechanism as well as the atomic structure of the fibril assembly. Based on the available information possible therapies are also surveyed.
Topics: Amyloidosis; Dimerization; Genetic Variation; Humans; Models, Molecular; Prealbumin; Protein Conformation
PubMed: 10940233
DOI: 10.1006/jsbi.2000.4273 -
Journal of Molecular Biology Aug 2012Transthyretin (TTR) is one of the many proteins that are known to misfold and aggregate (i.e., undergo amyloidogenesis) in vivo. The process of TTR amyloidogenesis... (Review)
Review
Transthyretin (TTR) is one of the many proteins that are known to misfold and aggregate (i.e., undergo amyloidogenesis) in vivo. The process of TTR amyloidogenesis causes nervous system and/or heart pathology. While several of these maladies are associated with mutations that destabilize the native TTR quaternary and/or tertiary structure, wild-type TTR amyloidogenesis also leads to the degeneration of postmitotic tissue. Over the past 20 years, much has been learned about the factors that influence the propensity of TTR to aggregate. This biophysical information led to the development of a therapeutic strategy, termed "kinetic stabilization," to prevent TTR amyloidogenesis. This strategy afforded the drug tafamidis which was recently approved by the European Medicines Agency for the treatment of TTR familial amyloid polyneuropathy, the most common familial TTR amyloid disease. Tafamidis is the first and currently the only medication approved to treat TTR familial amyloid polyneuropathy. Here we review the biophysical basis for the kinetic stabilization strategy and the structure-based drug design effort that led to this first-in-class pharmacologic agent.
Topics: Amyloidosis; Animals; Drug Approval; Humans; Kinetics; Models, Molecular; Prealbumin; Protein Conformation
PubMed: 22244854
DOI: 10.1016/j.jmb.2011.12.060 -
The New England Journal of Medicine Sep 2023
Topics: Humans; Prealbumin; Antibodies
PubMed: 37754296
DOI: 10.1056/NEJMc2309584 -
Proceedings of the National Academy of... Feb 1978Gel filtration of fresh human serum revealed that over 95% of the thymic-hormone-like activity was present in the fraction representing the total albumin and prealbumin....
Gel filtration of fresh human serum revealed that over 95% of the thymic-hormone-like activity was present in the fraction representing the total albumin and prealbumin. Further studies demonstrated that the activity resided in the prealbumin fraction; albumin was inactive. Prealbumin was isolated from Cohn fraction IV-1 of pooled human plasma by extraction with aqueous buffer, fractionation with (NH4)2SO4, gel filtration on Sephadex G-150, and preparative disc gel electrophoresis. The final product was homogeneous by analytical gel electrophoresis was 40,000 times more active than the starting material in an azathioprine-sensitive rosette assay. Physical and chemical characterization studies showed that the isolated product was identical to authentic human plasma prealbumin. Isolation of the prealbumin fraction from sera of adult thymectomized mice revealed that the rosette activity was substantially lower than that isolated from sera of normal mice, suggesting a thymic dependence of the prealbumin activity. In vitro and in vivo bioassays of the fraction obtained prior to the final step of the purification procedure support the conclusion that prealbumin exhibits thymic hormone-like activity.
Topics: Animals; Azathioprine; Humans; Male; Mice; Mice, Inbred C57BL; Prealbumin; Rosette Formation; Serum Albumin; Spleen; Thymectomy; Thymosin; Thymus Hormones
PubMed: 273245
DOI: 10.1073/pnas.75.2.823 -
Clinical Chemistry and Laboratory... 2007A large number of circumstances are associated with reduced serum concentrations of transthyretin (TTR), or prealbumin. The most common of these is the acute phase...
A large number of circumstances are associated with reduced serum concentrations of transthyretin (TTR), or prealbumin. The most common of these is the acute phase response, which may be due to inflammation, malignancy, trauma, or many other disorders. Some studies have shown a decrease in hospital stay with nutritional therapy based on TTR concentrations, but many recent studies have shown that concentrations of albumin, transferrin, and transthyretin correlate with severity of the underlying disease rather than with anthropometric indicators of hypo- or malnutrition. There are few if any conditions in which the concentration of this protein by itself is more helpful in diagnosis, prognosis, or follow up than are other clinical findings. In the majority of cases, the serum concentration of C-reactive protein is adequate for detection and monitoring of acute phase responses and for prognosis. Although over diagnosis and treatment of presumed protein energy malnutrition is probably not detrimental to most patients, the failure to detect other causes of decreased concentrations (such as serious bacterial infections or malignancy) of the so-called visceral or hepatic proteins could possibly result in increased morbidity or even mortality. In addition to these caveats, assays for TTR have a relatively high level of uncertainty ("imprecision"). Clinical evaluation--history and physical examination--should remain the mainstay of nutritional assessment.
Topics: Adolescent; Adult; Biomarkers; Blood Proteins; Child; Child, Preschool; Genetic Variation; Humans; Infant; Infant, Newborn; Inflammation; Malnutrition; Middle Aged; Prealbumin; Reference Values
PubMed: 17378745
DOI: 10.1515/CCLM.2007.051 -
Advances in Protein Chemistry 1997Human transthyretin (TTR) can be transformed into amyloid fibrils by partial acid denaturation to yield a monomeric amyloidogenic intermediate that self-associates into... (Review)
Review
Human transthyretin (TTR) can be transformed into amyloid fibrils by partial acid denaturation to yield a monomeric amyloidogenic intermediate that self-associates into amyloid through quaternary structural intermediates, which are identified by sedimentation velocity methods. The monomeric amyloidogenic intermediate has substantial beta-sheet structure with a nonnative but intact tertiary structure as discerned from spectroscopic methods. Proteolysis sensitivity studies suggest that the C-strand-loop-D-strand portion of TTR becomes disordered and moves away from the core of the beta-sandwich fold upon formation of the monomeric amyloidogenic intermediate over the pH range 5.1-3.9. The single site mutations that are associated with early onset amyloid disease [familial amyloid polyneuropathy (FAP)] function by destabilizing tetrameric TTR. Under mild denaturing conditions, the FAP variants populate the monomeric amyloidogenic intermediate conformation, which assembles into amyloid, whereas wild-type TTR remains tetrameric and nonamyloidogenic. The FAP mutations do not significantly alter the native folded structure; instead, they appear to act by making the thermodynamics and perhaps the kinetics more favorable for formation of the amyloidogenic intermediate. Suppressor mutations have also been characterized that strongly stabilize tetrameric TTR and disfavor the formation of the monomeric amyloidogenic intermediate, thus inhibiting amyloid formation. The mechanistic details characterizing transthyretin amyloid fibril formation available from the biophysical studies outlined within have been utilized to develop a new therapeutic strategy for intervention in human amyloid disease. This approach features small molecules that bind with high affinity to the normal fold of transthyretin, inhibiting the quaternary and tertiary structural changes associated with the formation of the monomeric amyloidogenic intermediate that self-assembles into amyloid. Ligand binding to TTR stabilizes the native tetrameric fold, which is nonamyloidogenic.
Topics: Amyloid; Animals; Humans; Prealbumin; Protein Conformation; Protein Structure, Tertiary
PubMed: 9338081
DOI: 10.1016/s0065-3233(08)60321-6