Genomes and Genes
Summary: Proteolytic enzymes that are involved in the conversion of protein precursors such as peptide prohormones into PEPTIDE HORMONES. Some are ENDOPEPTIDASES, some are EXOPEPTIDASES.
- Abifadel M, Rabes J, Jambart S, Halaby G, Gannage Yared M, Sarkis A, et al. The molecular basis of familial hypercholesterolemia in Lebanon: spectrum of LDLR mutations and role of PCSK9 as a modifier gene. Hum Mutat. 2009;30:E682-91 pubmed publisher..Thus, by studying for the first time the impact of PCSK9 polymorphism on LDL-cholesterol levels of FH patients carrying a same LDLR mutation, we show that PCSK9 might constitute a modifier gene in familial hypercholesterolemia. ..
- Du F, Hui Y, Zhang M, Linton M, Fazio S, Fan D. Novel domain interaction regulates secretion of proprotein convertase subtilisin/kexin type 9 (PCSK9) protein. J Biol Chem. 2011;286:43054-61 pubmed publisher..These results show a previously unrecognized domain interaction as a critical determinant in PCSK9 secretion and function. This knowledge should fuel efforts to develop novel approaches to PCSK9 inhibition. ..
- Davignon J, Dubuc G. Statins and ezetimibe modulate plasma proprotein convertase subtilisin kexin-9 (PCSK9) levels. Trans Am Clin Climatol Assoc. 2009;120:163-73 pubmed
- Seidah N. Proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors in the treatment of hypercholesterolemia and other pathologies. Curr Pharm Des. 2013;19:3161-72 pubmed..This opens the door to novel applications of PCSK9 inhibitors/silencers in cancer/metastasis. ..
- Canuel M, Sun X, Asselin M, Paramithiotis E, Prat A, Seidah N. Proprotein convertase subtilisin/kexin type 9 (PCSK9) can mediate degradation of the low density lipoprotein receptor-related protein 1 (LRP-1). PLoS ONE. 2013;8:e64145 pubmed publisher..Identification of PCSK9 targets should allow a better understanding of the consequences of PCSK9 inhibition for lowering LDLc and tumor metastasis. ..
- Lei X, Shi F, Basu D, Huq A, Routhier S, Day R, et al. Proteolytic processing of angiopoietin-like protein 4 by proprotein convertases modulates its inhibitory effects on lipoprotein lipase activity. J Biol Chem. 2011;286:15747-56 pubmed publisher..ANGPTL4 protein is then proteolytically cleaved into several forms by proprotein convertases (PCs)...
- Kosenko T, Golder M, Leblond G, Weng W, Lagace T. Low density lipoprotein binds to proprotein convertase subtilisin/kexin type-9 (PCSK9) in human plasma and inhibits PCSK9-mediated low density lipoprotein receptor degradation. J Biol Chem. 2013;288:8279-88 pubmed publisher..These data suggest that association of PCSK9 with LDL particles in plasma lowers the ability of PCSK9 to bind to cell surface LDLRs, thereby blunting PCSK9-mediated LDLR degradation. ..
- Becker G, Sielaff F, Than M, Lindberg I, Routhier S, Day R, et al. Potent inhibitors of furin and furin-like proprotein convertases containing decarboxylated P1 arginine mimetics. J Med Chem. 2010;53:1067-75 pubmed publisherFurin belongs to the family of proprotein convertases (PCs) and is involved in numerous normal physiological and pathogenic processes, such as viral propagation, bacterial toxin activation, cancer, and metastasis...
- Lo Surdo P, Bottomley M, Calzetta A, Settembre E, Cirillo A, Pandit S, et al. Mechanistic implications for LDL receptor degradation from the PCSK9/LDLR structure at neutral pH. EMBO Rep. 2011;12:1300-5 pubmed publisher..Thus, PCSK9 seems to hold LDLR in an extended conformation and to interfere with conformational rearrangements required for LDLR recycling. ..
- Liu J, Afroza H, Rader D, Jin W. Angiopoietin-like protein 3 inhibits lipoprotein lipase activity through enhancing its cleavage by proprotein convertases. J Biol Chem. 2010;285:27561-70 pubmed publisher..paired amino acid converting enzyme-4 (PACE4), and LPL, we demonstrated that the cleavage of LPL by proprotein convertases is an inactivation process, similar to that seen for endothelial lipase cleavage...
- Demidyuk I, Shubin A, Gasanov E, Kurinov A, Demkin V, Vinogradova T, et al. Alterations in gene expression of proprotein convertases in human lung cancer have a limited number of scenarios. PLoS ONE. 2013;8:e55752 pubmed publisherb>Proprotein convertases (PCs) is a protein family which includes nine highly specific subtilisin-like serine endopeptidases in mammals...
- Dong B, Wu M, Cao A, Li H, Liu J. Suppression of Idol expression is an additional mechanism underlying statin-induced up-regulation of hepatic LDL receptor expression. Int J Mol Med. 2011;27:103-10 pubmed publisher..This may contribute to the hypocholesterolemic effects of statins observed in clinical settings. ..
- Dong B, Wu M, Li H, Kraemer F, Adeli K, Seidah N, et al. Strong induction of PCSK9 gene expression through HNF1alpha and SREBP2: mechanism for the resistance to LDL-cholesterol lowering effect of statins in dyslipidemic hamsters. J Lipid Res. 2010;51:1486-95 pubmed publisher..Thus, the net balance is in favor of PCSK9-induced degradation of LDLR in the hamster liver, abrogating the effect of rosuvastatin on LDL-C lowering. ..
- Urata S, Yun N, Pasquato A, Paessler S, Kunz S, de la Torre J. Antiviral activity of a small-molecule inhibitor of arenavirus glycoprotein processing by the cellular site 1 protease. J Virol. 2011;85:795-803 pubmed publisher..Our findings support the feasibility of using small-molecule inhibitors of S1P-mediated processing of arenavirus GPC as a novel antiviral strategy. ..
- Singh H, Heng S, Nicholls P, Li Y, Tai L, Jobling T, et al. Proprotein convertases in post-menopausal endometrial cancer: distinctive regulation and non-invasive diagnosis. Biochem Biophys Res Commun. 2012;419:809-14 pubmed publisherb>Proprotein convertases (PCs) play critical roles in cleaving precursor proteins (growth factors, hormones, receptors and adhesion molecules) for activation. PCs are implicated in a number of cellular functions, including oncogenesis...
- Lakoski S, Lagace T, Cohen J, Horton J, Hobbs H. Genetic and metabolic determinants of plasma PCSK9 levels. J Clin Endocrinol Metab. 2009;94:2537-43 pubmed publisher..Although levels of PCSK9 correlate with plasma levels of LDL-C, they account for only a small proportion of the variation in the levels of this lipoprotein. ..
- Duff C, Hooper N. PCSK9: an emerging target for treatment of hypercholesterolemia. Expert Opin Ther Targets. 2011;15:157-68 pubmed publisher..However, further research is required to fully understand the biological role of PCSK9 and whether its inhibition may have adverse effects in certain groups of patients, for example, those with liver disease. ..
- Yamamoto T, Lu C, Ryan R. A two-step binding model of PCSK9 interaction with the low density lipoprotein receptor. J Biol Chem. 2011;286:5464-70 pubmed publisher..4. Thus, CT domain interaction with the LBD of the LDLR at endosomal pH constitutes a second step in the PCSK9-mediated LDLR binding that leads to receptor degradation. ..
- Lalou C, Scamuffa N, Mourah S, Plassa F, Podgorniak M, Soufir N, et al. Inhibition of the proprotein convertases represses the invasiveness of human primary melanoma cells with altered p53, CDKN2A and N-Ras genes. PLoS ONE. 2010;5:e9992 pubmed publisher..primary human melanoma M10 cells with altered p53, CDKN2A and N-Ras genes, we found that inhibition of the proprotein convertases (PCs), enzymes involved in the proteolytic activation of various cancer-related protein precursors ..
- Sharotri V, Collier D, Olson D, Zhou R, Snyder P. Regulation of epithelial sodium channel trafficking by proprotein convertase subtilisin/kexin type 9 (PCSK9). J Biol Chem. 2012;287:19266-74 pubmed publisher..By reducing ENaC channel number, PCSK9 could modulate epithelial Na(+) absorption, a major contributor to blood pressure control. ..
- Chretien M. My road to Damascus: how I converted to the prohormone theory and the proprotein convertases. Biochem Cell Biol. 2012;90:750-68 pubmed publisher..It implied the existence of specific endoproteolytic enzymes. These proprotein convertases were discovered in 1990...
- Humphries S, Neely R, Whittall R, Troutt J, Konrad R, Scartezini M, et al. Healthy individuals carrying the PCSK9 p.R46L variant and familial hypercholesterolemia patients carrying PCSK9 p.D374Y exhibit lower plasma concentrations of PCSK9. Clin Chem. 2009;55:2153-61 pubmed publisher..In treated FH patients, a low plasma PCSK9 concentration does not appear to be a useful screening tool for identifying novel PCSK9 mutations. ..
- Benjannet S, Hamelin J, Chretien M, Seidah N. Loss- and gain-of-function PCSK9 variants: cleavage specificity, dominant negative effects, and low density lipoprotein receptor (LDLR) degradation. J Biol Chem. 2012;287:33745-55 pubmed..All Asp(374) mutations resulted in similar gain-of-function activity on the LDLR except that D374E was as active as native PCSK9, D374G was relatively less active, and D374N and D374P were completely inactive. ..
- Miyazawa H, Honda T, Miyauchi S, Domon H, Okui T, Nakajima T, et al. Increased serum PCSK9 concentrations are associated with periodontal infection but do not correlate with LDL cholesterol concentration. Clin Chim Acta. 2012;413:154-9 pubmed publisher..Periodontal infection upregulates PCSK9 production. However, further studies are required to elucidate how periodontal infection affects PCSK9 concentrations and subsequent lipid metabolism. ..
- Giugliano R, Desai N, Kohli P, Rogers W, Somaratne R, Huang F, et al. Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 in combination with a statin in patients with hypercholesterolaemia (LAPLACE-TIMI 57): a randomised, placebo-controlled, dose-ranging, phase . Lancet. 2012;380:2007-17 pubmed publisher..The results suggest that PCSK9 inhibition could be a new model in lipid management. Inhibition of PCSK9 warrants assessment in phase 3 clinical trials. Amgen. ..
- Popkin D, Teijaro J, Sullivan B, Urata S, Rutschmann S, de la Torre J, et al. Hypomorphic mutation in the site-1 protease Mbtps1 endows resistance to persistent viral infection in a cell-specific manner. Cell Host Microbe. 2011;9:212-222 pubmed publisher..These results support in vivo targeting of Mbtps1 in the treatment of arenavirus infections and demonstrate a critical role for dendritic cells in persistent viral infections...
- Seidah N, Poirier S, Denis M, Parker R, Miao B, Mapelli C, et al. Annexin A2 is a natural extrahepatic inhibitor of the PCSK9-induced LDL receptor degradation. PLoS ONE. 2012;7:e41865 pubmed publisher..Finally, we identified an AnxA2 coding polymorphism, V98L, that correlates with lower circulating levels of PCSK9 thereby extending our results on the physiological role of AnxA2 in humans. ..
- Koo B, Kim H, Park M, Jeon O, Kim D. Membrane type-1 matrix metalloprotease-independent activation of pro-matrix metalloprotease-2 by proprotein convertases. FEBS J. 2009;276:6271-84 pubmed publisher..propeptide processing of matrix metalloprotease-2 in HEK293F and various tumor cell lines, and show that proprotein convertases can mediate the processing intracellularly as well as extracellularly...
- Lakoski S, Xu F, Vega G, Grundy S, Chandalia M, Lam C, et al. Indices of cholesterol metabolism and relative responsiveness to ezetimibe and simvastatin. J Clin Endocrinol Metab. 2010;95:800-9 pubmed publisher..Responsiveness to simvastatin and ezetimibe were highly correlated, suggesting that factors downstream of the primary sites of action of these drugs are a major determinant of response. ..
- Sun H, Samarghandi A, Zhang N, Yao Z, Xiong M, Teng B. Proprotein convertase subtilisin/kexin type 9 interacts with apolipoprotein B and prevents its intracellular degradation, irrespective of the low-density lipoprotein receptor. Arterioscler Thromb Vasc Biol. 2012;32:1585-95 pubmed publisher..Furthermore, our results indicate that targeting PCSK9 expression represents a new paradigm in therapeutic intervention against hyperlipidemia. ..
- Southey B, RODRIGUEZ ZAS S, Sweedler J. Characterization of the prohormone complement in cattle using genomic libraries and cleavage prediction approaches. BMC Genomics. 2009;10:228 pubmed publisher..The complete set of cattle prohormone sequences identified and the cleavage prediction approaches are available at http://neuroproteomics.scs.uiuc.edu/neuropred.html. ..
- Koren M, Scott R, Kim J, Knusel B, Liu T, Lei L, et al. Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 as monotherapy in patients with hypercholesterolaemia (MENDEL): a randomised, double-blind, placebo-controlled, phase 2 study. Lancet. 2012;380:1995-2006 pubmed publisher..The results of our study support the further assessment of AMG 145 in long-term studies with larger and more diverse populations including patients with documented statin intolerance. Amgen. ..
- Marschner K, Kollmann K, Schweizer M, Braulke T, Pohl S. A key enzyme in the biogenesis of lysosomes is a protease that regulates cholesterol metabolism. Science. 2011;333:87-90 pubmed publisher..Thus, S1P functions in the biogenesis of lysosomes, and lipid-independent phenotypes of S1P deficiency may be caused by lysosomal dysfunction...
- Cariou B, Le Bras M, Langhi C, Le May C, Guyomarc h Delasalle B, Krempf M, et al. Association between plasma PCSK9 and gamma-glutamyl transferase levels in diabetic patients. Atherosclerosis. 2010;211:700-2 pubmed publisher..PCSK9 level was independently associated with GGT level in diabetic patients, suggesting potential interaction between PCSK9 and liver function. ..
- Dias C, Shaywitz A, Wasserman S, Smith B, Gao B, Stolman D, et al. Effects of AMG 145 on low-density lipoprotein cholesterol levels: results from 2 randomized, double-blind, placebo-controlled, ascending-dose phase 1 studies in healthy volunteers and hypercholesterolemic subjects on statins. J Am Coll Cardiol. 2012;60:1888-98 pubmed publisher
- Pasquato A, Burri D, Traba E, Hanna El Daher L, Seidah N, Kunz S. Arenavirus envelope glycoproteins mimic autoprocessing sites of the cellular proprotein convertase subtilisin kexin isozyme-1/site-1 protease. Virology. 2011;417:18-26 pubmed publisher..The data suggest that arenavirus GPCs evolved to mimic SKI-1/S1P autoprocessing sites, likely ensuring efficient cleavage and perhaps avoiding competition with SKI-1/S1P's cellular substrates. ..
- Zandberg W, Benjannet S, Hamelin J, Pinto B, Seidah N. N-glycosylation controls trafficking, zymogen activation and substrate processing of proprotein convertases PC1/3 and subtilisin kexin isozyme-1. Glycobiology. 2011;21:1290-300 pubmed publisherThe limited proteolysis of proteins by the proprotein convertases (PCs) is a common means of producing bioactive proteins or peptides...
- Abifadel M, Guerin M, Benjannet S, Rabes J, Le Goff W, Julia Z, et al. Identification and characterization of new gain-of-function mutations in the PCSK9 gene responsible for autosomal dominant hypercholesterolemia. Atherosclerosis. 2012;223:394-400 pubmed publisher..These data further contribute to the characterization of PCSK9 mutations and to better understanding of the impact on cholesterol metabolism of this new therapeutic target. ..
- ..These PCSK9 inhibitors are now tested in larger phase III studies to provide insights into the long-term safety and clinical efficacy of this very promising approach. ..
- Seidah N, Prat A. The biology and therapeutic targeting of the proprotein convertases. Nat Rev Drug Discov. 2012;11:367-83 pubmedThe mammalian proprotein convertases constitute a family of nine secretory serine proteases that are related to bacterial subtilisin and yeast kexin...
- Delfino K, Southey B, Sweedler J, Rodriguez Zas S. Genome-wide census and expression profiling of chicken neuropeptide and prohormone convertase genes. Neuropeptides. 2010;44:31-44 pubmed publisher..Our complete survey and characterization facilitates understanding of neuropeptides genes in the chicken, an animal of importance to biomedical and agricultural research. ..
- Norata G, Garlaschelli K, Grigore L, Raselli S, Tramontana S, Meneghetti F, et al. Effects of PCSK9 variants on common carotid artery intima media thickness and relation to ApoE alleles. Atherosclerosis. 2010;208:177-82 pubmed publisher..PCSK9 plays a key role in plasma cholesterol metabolism by modulating the expression of LDL receptors...
- Liang H, Chaparro Riggers J, Strop P, Geng T, Sutton J, Tsai D, et al. Proprotein convertase substilisin/kexin type 9 antagonism reduces low-density lipoprotein cholesterol in statin-treated hypercholesterolemic nonhuman primates. J Pharmacol Exp Ther. 2012;340:228-36 pubmed publisher..Our data demonstrate that anti-PCSK9 antibody is a promising LDL-C-lowering agent that is both efficacious and potentially additive to current therapies. ..
- Sun X, Essalmani R, Day R, Khatib A, Seidah N, Prat A. Proprotein convertase subtilisin/kexin type 9 deficiency reduces melanoma metastasis in liver. Neoplasia. 2012;14:1122-31 pubmed..Our findings show that PCSK9 deficiency reduces liver metastasis by its ability to lower cholesterol levels and by possibly enhancing TNF?-mediated apoptosis. ..
- Brandl K, Rutschmann S, Li X, Du X, Xiao N, Schnabl B, et al. Enhanced sensitivity to DSS colitis caused by a hypomorphic Mbtps1 mutation disrupting the ATF6-driven unfolded protein response. Proc Natl Acad Sci U S A. 2009;106:3300-5 pubmed publisher..Experiments with bone marrow chimeric mice reveal a requirement for S1P in nonhematopoietic cells, without which a diminished UPR and colitis develop. ..
- Stein E, Swergold G. Potential of proprotein convertase subtilisin/kexin type 9 based therapeutics. Curr Atheroscler Rep. 2013;15:310 pubmed publisher..Larger and much longer phase 3 trials are now in progress to assess the long-term tolerability, safety, and impact on cardiovascular disease events of these very effective LDLc lowering compounds. ..
- Persson L, Cao G, Stahle L, Sjöberg B, Troutt J, Konrad R, et al. Circulating proprotein convertase subtilisin kexin type 9 has a diurnal rhythm synchronous with cholesterol synthesis and is reduced by fasting in humans. Arterioscler Thromb Vasc Biol. 2010;30:2666-72 pubmed publisher..In addition to this sterol-mediated regulation, additional effects on LDL receptors may be mediated by hormones directly influencing PCSK9. ..
- Zhang Y, Eigenbrot C, Zhou L, Shia S, Li W, Quan C, et al. Identification of a small peptide that inhibits PCSK9 protein binding to the low density lipoprotein receptor. J Biol Chem. 2014;289:942-55 pubmed publisher..Pep2-8 bound to PCSK9 with a KD of 0.7 ?m but did not bind to other proprotein convertases. It fully restored LDL receptor surface levels and LDL particle uptake in PCSK9-treated HepG2 cells...
- Schiele F, Park J, Redemann N, Luippold G, Nar H. An antibody against the C-terminal domain of PCSK9 lowers LDL cholesterol levels in vivo. J Mol Biol. 2014;426:843-52 pubmed publisher..Blocking of the CTD is sufficient to partially inhibit PCSK9 function. Antibodies binding the CTD of PCSK9 may thus be advantageous in patients that do not tolerate complete inhibition of PCSK9. ..
- Chaparro Riggers J, Liang H, DeVay R, Bai L, Sutton J, Chen W, et al. Increasing serum half-life and extending cholesterol lowering in vivo by engineering antibody with pH-sensitive binding to PCSK9. J Biol Chem. 2012;287:11090-7 pubmed publisher..Engineered pH-sensitive antibodies may enable less frequent or lower dosing of antibodies hampered by target-mediated clearance and high antigen load. ..
- Mbikay M, Sirois F, Mayne J, Wang G, Chen A, Dewpura T, et al. PCSK9-deficient mice exhibit impaired glucose tolerance and pancreatic islet abnormalities. FEBS Lett. 2010;584:701-6 pubmed publisher..Collectively, these observations suggest that PCSK9 may be necessary for the normal function of pancreatic islets. ..
- Mousavi S, Berge K, Leren T. The unique role of proprotein convertase subtilisin/kexin 9 in cholesterol homeostasis. J Intern Med. 2009;266:507-19 pubmed publisher..However, PCSK9 has also recently been shown to mediate down-regulation of surface receptors other than the LDLR, suggesting that it may have much broader roles than initially thought. ..
- Tian S, Jianhua W. Comparative study of the binding pockets of mammalian proprotein convertases and its implications for the design of specific small molecule inhibitors. Int J Biol Sci. 2010;6:89-95 pubmedb>Proprotein convertases are enzymes that proteolytically cleave protein precursors in the secretory pathway to yield functional proteins...
- Blom D, Hala T, Bolognese M, Lillestol M, Toth P, Burgess L, et al. A 52-week placebo-controlled trial of evolocumab in hyperlipidemia. N Engl J Med. 2014;370:1809-19 pubmed publisher..Funded by Amgen; DESCARTES ClinicalTrials.gov number, NCT01516879.). ..
- Browning J, Horton J. Fasting reduces plasma proprotein convertase, subtilisin/kexin type 9 and cholesterol biosynthesis in humans. J Lipid Res. 2010;51:3359-63 pubmed publisher..Inasmuch as cholesterol synthesis and PCSK9 are both regulated by SREBP-2, these results suggest that plasma PCSK9 levels may serve as a surrogate marker of hepatic SREBP-2 activity in humans. ..
- Seidah N. The proprotein convertases, 20 years later. Methods Mol Biol. 2011;768:23-57 pubmed publisherThe proprotein convertases (PCs) are secretory mammalian serine proteinases related to bacterial subtilisin-like enzymes. The family of PCs comprises nine members, PC1/3, PC2, furin, PC4, PC5/6, PACE4, PC7, SKI-1/S1P, and PCSK9 (Fig. 3.1)...
- Benjannet S, Saavedra Y, Hamelin J, Asselin M, Essalmani R, Pasquato A, et al. Effects of the prosegment and pH on the activity of PCSK9: evidence for additional processing events. J Biol Chem. 2010;285:40965-78 pubmed publisher..These data enhance our understanding of the functional role of the acidic prosegment and on the effect of pH in the regulation of PCSK9 activity. ..
- Mayne J, Dewpura T, Raymond A, Bernier L, Cousins M, Ooi T, et al. Novel loss-of-function PCSK9 variant is associated with low plasma LDL cholesterol in a French-Canadian family and with impaired processing and secretion in cell culture. Clin Chem. 2011;57:1415-23 pubmed publisher..Collectively, our results demonstrate that the PCSK9-Q152H variant markedly lowers plasma PCSK9 and LDLC concentrations in heterozygous carriers via decreased autocatalytic processing and secretion, and hence, inactivity on the LDLR. ..
- Li H, Dong B, Park S, Lee H, Chen W, Liu J. Hepatocyte nuclear factor 1alpha plays a critical role in PCSK9 gene transcription and regulation by the natural hypocholesterolemic compound berberine. J Biol Chem. 2009;284:28885-95 pubmed publisher..This is the first described example of SREBP pairing with HNF1 to control an important regulatory pathway in cholesterol homeostasis. This work also provides a mechanism for how BBR suppresses PCSK9 transcription. ..
- Holla Ø, Laerdahl J, Strøm T, Tveten K, Cameron J, Berge K, et al. Removal of acidic residues of the prodomain of PCSK9 increases its activity towards the LDL receptor. Biochem Biophys Res Commun. 2011;406:234-8 pubmed publisher..The underlying mechanism could involve the binding of this peptide segment to positively charged structures which are important for PCSK9's activity. One possible candidate could be the histidine-rich C-terminal domain of PCSK9. ..
- Cariou B, Le May C, Costet P. Clinical aspects of PCSK9. Atherosclerosis. 2011;216:258-65 pubmed publisher..Finally, we present a brief overview of the available therapeutic strategies to inhibit PCSK9. ..
- Maisa A, Stroher U, Klenk H, Garten W, Strecker T. Inhibition of Lassa virus glycoprotein cleavage and multicycle replication by site 1 protease-adapted alpha(1)-antitrypsin variants. PLoS Negl Trop Dis. 2009;3:e446 pubmed publisher..Therefore, we tested in this study the concept of using S1P as a target to block efficient virus replication...
- Pasquato A, Ramos da Palma J, Galan C, Seidah N, Kunz S. Viral envelope glycoprotein processing by proprotein convertases. Antiviral Res. 2013;99:49-60 pubmed publisherThe proprotein convertases (PCs) are a family of nine mammalian enzymes that play key roles in the maintenance of cell homeostasis by activating or inactivating proteins via limited proteolysis under temporal and spatial control...
- Abifadel M, Pakradouni J, Collin M, Samson Bouma M, Varret M, Rabes J, et al. Strategies for proprotein convertase subtilisin kexin 9 modulation: a perspective on recent patents. Expert Opin Ther Pat. 2010;20:1547-71 pubmed publisher..They constitute very promising approaches to reducing cholesterol levels and coronary heart disease. ..
- Baass A, Dubuc G, Tremblay M, Delvin E, O Loughlin J, Levy E, et al. Plasma PCSK9 is associated with age, sex, and multiple metabolic markers in a population-based sample of children and adolescents. Clin Chem. 2009;55:1637-45 pubmed publisher..A novel finding is that PCSK9 is associated with fasting insulinemia, which suggests that PCSK9 could play a role in the development of dyslipidemia associated with the metabolic syndrome. . ..
- Chan J, Piper D, Cao Q, Liu D, King C, Wang W, et al. A proprotein convertase subtilisin/kexin type 9 neutralizing antibody reduces serum cholesterol in mice and nonhuman primates. Proc Natl Acad Sci U S A. 2009;106:9820-5 pubmed publisher..In cynomolgus monkeys, a single injection of mAb1 reduces serum LDL-C by 80%, and a significant decrease is maintained for 10 days. We conclude that anti-PCSK9 antibodies may be effective therapeutics for treating hypercholesterolemia. ..
- Sullivan D, Olsson A, Scott R, Kim J, Xue A, Gebski V, et al. Effect of a monoclonal antibody to PCSK9 on low-density lipoprotein cholesterol levels in statin-intolerant patients: the GAUSS randomized trial. JAMA. 2012;308:2497-506 pubmed publisher..TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01375764. ..
- Futema M, Plagnol V, Whittall R, Neil H, Humphries S. Use of targeted exome sequencing as a diagnostic tool for Familial Hypercholesterolaemia. J Med Genet. 2012;49:644-9 pubmed publisher..However, the poor coverage of gene promoters and repetitive, or GC-rich sequences, remains problematic, and validation of all identified variants is currently required. ..
- Stein E, Gipe D, Bergeron J, Gaudet D, Weiss R, Dufour R, et al. Effect of a monoclonal antibody to PCSK9, REGN727/SAR236553, to reduce low-density lipoprotein cholesterol in patients with heterozygous familial hypercholesterolaemia on stable statin dose with or without ezetimibe therapy: a phase 2 randomised cont. Lancet. 2012;380:29-36 pubmed publisher..REGN727 has the potential to provide optimum control of LDL-C in patients with this disorder. Sanofi US and Regeneron Pharmaceuticals Incorporated. ..
- Zhang L, McCabe T, Condra J, Ni Y, Peterson L, Wang W, et al. An anti-PCSK9 antibody reduces LDL-cholesterol on top of a statin and suppresses hepatocyte SREBP-regulated genes. Int J Biol Sci. 2012;8:310-27 pubmed publisher..Our results suggest that antibodies targeting PCSK9 could provide patients powerful LDL lowering efficacy on top of statins, and lower cardiovascular risk. ..
- Thompson J, Hyde C, Wood L, Paciga S, Hinds D, Cox D, et al. Comprehensive whole-genome and candidate gene analysis for response to statin therapy in the Treating to New Targets (TNT) cohort. Circ Cardiovasc Genet. 2009;2:173-81 pubmed publisher..Among SNPs tested with an allele frequency of at least 5%, only SNPs in apoE are found to influence statin response significantly. Less frequent variants in PCSK9 and smaller effect sizes in SNPs in HMGCR were also revealed. ..
- Aung L, Yin R, Miao L, Hu X, Yan T, Cao X, et al. The proprotein convertase subtilisin/kexin type 9 gene E670G polymorphism and serum lipid levels in the Guangxi Bai Ku Yao and Han populations. Lipids Health Dis. 2011;10:5 pubmed publisher..The G allele carriers had higher serum HDL-C and ApoAI levels in males, and lower serum ApoB levels and higher the ApoAI/ApoB ratio in females than the G allele noncarriers. ..