DOCSLIB.ORG

(12) Patent Application Publication (10) Pub. No.: US 2011/0166063 A1 Bossard Et Al

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
(12) Patent Application Publication (10) Pub. No.: US 2011/0166063 A1 Bossard Et Al US 2011 0166063A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/0166063 A1 BOSsard et al. (43) Pub. Date: Jul. 7, 2011 (54) POLYMER CONJUGATES OF THERAPEUTIC Related U.S. Application Data PEPTIDES (60) Provisional application No. 61/192,672, filed on Sep. 19, 2008, provisional application No. 61/208,089, (75) Inventors: Mary J. Bossard, Madison, AL filed on Feb. 18, 2009, provisional application No. (US); Steven O. Roczniak, 61/153,966, filed on Feb. 19, 2009. Greensboro, NC (US); Harold Zappe, Harvest, AL (US); Yujun Publication Classification Wang, Madison, AL (US); Ping (51) Int. Cl. Zhang, Madison, AL (US); Dawei A638/28 (2006.01) Sheng, Madison, AL (US); C. A638/16 (2006.01) Simone Jude-Fishburn, Redwood A638/08 (2006.01) City, CA (US); Elizabeth Louise A638/06 (2006.01) Minamitani, Lacey's Spring, AL A638/07 (2006.01) (US); Xiaofeng Liu, Union City, A638/10 (2006.01) CA (US); Haim Moskowitz, San C07K 5/08 (2006.01) Diego, CA (US); Dennis G. Fry, C07K 7/06 (2006.01) Huntsville, AL (US); Cherie F. Ali, C07K 7/08 (2006.01) Burlingame, CA (US); Christine C07K I4/00 (2006.01) Taylor Brew, Pacifica, CA (US) A6IP3/10 (2006.01) (52) U.S. Cl. ....... 514/5.9; 514/21.3; 514/21.2: 514/21.7; (73) Assignee: Nektar Therapeutics, San 514/21.6; 514/21.9; 514/21.8; 514/21.5; 530/303; Francisco, CA (US) 530/331; 530/330,530/329; 530/328; 530/327; 530/326; 530/324; 530/350 (21) Appl. No.: 13/119,297 (57) ABSTRACT (22) PCT Filed: Sep. 17, 2009 The invention provides peptides that are chemically modified by covalent attachment of a water-soluble oligomer. A con (86). PCT No.: PCT/US09/05.192 jugate of the invention, when administered by any of a num ber of administration routes, exhibits characteristics that are S371 (c)(1), different from the characteristics of the peptide not attached (2), (4) Date: Mar. 16, 2011 to the water-soluble oligomer. P es Mono 8sa 8. Conjugate s r c h S e 9 O OO 250 Volume (mL) Patent Application Publication Jul. 7, 2011 Sheet 1 of 84 US 2011/O166063 A1 2 4. O S 9 O es 5. Mono 8. Conjugate l4O S 2 e 9 O 150 2OO 250 Volume (ml) Figure KISS1.1 DAD-E. Sig38S, 16 Re-38C, GE LMKISSPEPTIFFGF2308A8-07-23 (3-53-530723.8Aloob) Figure KISS 1.2 Patent Application Publication Jul. 7, 2011 Sheet 2 of 84 US 2011/0166063 A1 340.25 --- 400 200 1776,028 too sess 20000 2sode Soo ssood 48-88 also Az Figure KISS 1.3 - UV1280nm - UV2225mm Cond ConC pH 14 13 KP-1 ButALD10K 12 W Coniugate O ---m Un-reacted KP-10 ml O 2O 40 80 BO 1OO 120 140 18O Figure KISS2.1 Patent Application Publication Jul. 7, 2011 Sheet 3 of 84 US 2011/O166063 A1 Figure KISS2.2 : : s 3 5 25 s f SEAllish t ---------------------T t t t at SN Quality Fac. Res. Entens. Area 2 is 00 0 104. 9. Figure 2.3 Patent Application Publication Jul. 7, 2011 Sheet 4 of 84 US 2011/O166063 A1 mAU T UV1280nm - UV2 225nm - Cond - Conc - pH - Un-reacted 1 -10 200 \ KP-10/But ALD30K 1000 A. Conjugate Figure KISS3.1 DAD1E, Sig-280.6 Ref-360,100, TT (11108 PRO.TY 1108 PRODUCT PURITY 2008-11-17-11-3005-050.0) AU Figure KISS3.2 Patent Application Publication Jul. 7, 2011 Sheet 5 of 84 US 2011/0166063 A1 rtiz SN Quality Fac. Rcs. Intens, Arca 3493.80s 349. s46ss 37.66 SS388 6629.ss 12. 72 4 696 9ss Figure KISS3.3 Figure KISS4.1 Patent Application Publication Jul. 7, 2011 Sheet 6 of 84 US 2011/O166063 A1 DAD1E, Sig=280,16Ref=360,100, TT (111108 PRO.TY111108 PRODUCT PURTY 2008-11-111-1143.008-09010) es s Figure KISS4.2 42038.83 o o w ". do raft SN Quality Fac. Res, latens. Aree 203,983 9. 49 to so. Oss Figure KISS4.3 Patent Application Publication Jul. 7, 2011 Sheet 7 of 84 US 2011/O166063 A1 AA Unreacted KP-10/SBC30K / / s SBC30K Conjugate N s \ Un-reacted KP-10 2 Unreacted d s O a Ne--- A ° N\1 Nis n-4 s A. A. A. As As A 3AS . S. 2 2s. ... " Figure KISS5.1 Figure KISS5.2 Patent Application Publication Jul. 7, 2011 Sheet 8 of 84 US 2011/O166063 A1 O DAD1E, Sig-280,s Refe380,100, TT (111g08 PRODUCT PURITY 11g08 PRODUCT PURTY 2008-11-1915.140205 na N 2 w |Marks: Figure KISS5.4 Patent Application Publication Jul. 7, 2011 Sheet 9 of 84 US 2011/O166063 A1 mono-mPEG2-Butyraldehyde 4KHKispeptin-san Un-reacted Figure KISS6.1 DAD1E, Sig-280.16 Ref=360,100, TT (111908 PRO.TY111908 PRODUCTPURITY 2008-11-1915-140204-0401.D) AU w 25 15 10 2.5 s 5 10 125 15 17.5 20 : Figure KISS6.2 Patent Application Publication Jul. 7, 2011 Sheet 10 of 84 US 2011/0166063 A1 Figure KISS6.3 ordat Yan2008Now OPButyradiok Corriff KP5By AD40K Coveyda i. st sn Quality Fac, Rea has Area 34) d is a a 12 co, was Frt p.r. go yr24.3a is 4 Figure KISS6.4 Patent Application Publication Jul. 7, 2011 Sheet 11 of 84 US 2011/O166063 A1 to KP10 1 O Ald1 OK-KP10 A Ald3OK-KP10 v KP13 0 KP54 O Ald-30K-KP13 O Ald-40K-KP54 A metastin log Conc M Figure KISS8.1 120 1 O CAC-4OK-KP1O 96.hr CAC-4OK-KP10 48hr CAC-4OK-KP1 O 96ht CAC-4OK-KP10 Ohr metastin log Conc M Figure KISS8.2 Patent Application Publication Jul. 7, 2011 Sheet 12 of 84 US 2011/O166063 A1 O SBC-3OK-KP1O 2hr SBC-30K-KP10 Ohr A metastin log (ConcM Figure KISS8.3 Patent Application Publication Jul. 7, 2011 Sheet 13 of 84 US 2011/O166063 A1 ^ me 215 mm | mus 280 mm ra f D1 and High-conjugate Mono-conjugate Volume (mL) WD assinosis. Soto Figure ZIC2.1 s s W s so so Figure Zic2.2 Patent Application Publication Jul. 7, 2011 Sheet 14 of 84 US 2011/O166063 A1 239).54 4000 6000 8. 2000) 2200 24 2s) 2800 300 3abo s4000 re Figure ZIC2.3 "sissiste-2.3TiSEATV ve -acetitectZick is er - gEg is guagers m T ' f T 215 mm TT- 280 mm t "I Diard High-conjugate E. and free PEG an --" - / W / a Mono-conjugate -/ ge M 1.A. \ Volune (un) Figure ZIC3.1 Patent Application Publication Jul. 7, 2011 Sheet 15 of 84 US 2011/O166063 A1 SS o 500 3. r U | /\- ----- ----H----------H Figure ZIC3.2 44479.53 30 2 10 r 3000 3SOOO 4000 also 50 550 so so occo Figure ZIC3.3 Patent Application Publication Jul. 7, 2011 Sheet 16 of 84 US 2011/O166063 A1 f 2 1 s 280 mm D and High-conjugate and free PEG Volumne in Li Figure ZIC4.1 Figure ZIC4.2 Patent Application Publication Jul. 7, 2011 Sheet 17 of 84 US 2011/0166063 A1 200 34209,596 1CO 50 00 3000 3200 34000 Soo 3800 40000 fe Patent Application Publication Jul. 7, 2011 Sheet 18 of 84 US 2011/O166063 A1 100 Ziconotide A Mono-mpG-20K-C2-FMOC-Zicono. 80 W Mono-mpEG-30K-SBA-Zicono. 60 0 Mono-mpEG-40K-CAC-FMOC-Zicono. 40 20 10-16 O 10-13 10-12 10-11 10-10 10-9 10-8 10-7 Log Inhibitor) (M) Ligand): 1.0e-11 Ko: 1.Oe-11 Figure ZIC6.1 Patent Application Publication Jul. 7, 2011 Sheet 19 of 84 US 2011/O166063 A1 Figure BIP1. Biphalin structure Figure BIP2.1 Patent Application Publication Jul. 7, 2011 Sheet 20 of 84 US 2011/O166063 A1 Figure BIP2.2 so 5291.467 558.75 5423.91 Soo,367 SBB. 92 - 5028,053 SS12.24 4982.4 5558,543 SB00704 sail|| || | 5644,888ye -4849,493 5688.995 4805,95 5733.29s- 4761.110 577,849 4718,828 4627,743 Figure BIP2.3 Patent Application Publication Jul. 7, 2011 Sheet 21 of 84 US 2011/O166063 A1 ec2cc 7Soboe YWoo: uvason is is Yst far. peogfiscegoeywoo; Rasos O 50 O 15 20 Figure BIP3.1 2, 4, 5, 800 10, 120 140. 6.00 8.0 20, 200 2.0 26.0 28.00 3000 Minutes RT Area 120722 2 2.355 560602 Figure BIP3.2 Patent Application Publication Jul. 7, 2011 Sheet 22 of 84 US 2011/O166063 A1 4358,531 21865,641 Figure BIP4.1 Patent Application Publication Jul. 7, 2011 Sheet 23 of 84 US 2011/0166063 A1 mu OO distristirubhirleridis S1) E228Ac. 2S35s CO S. D. S. M 120932 689892 319 4069 2214322092491496,81708a04 Figure BIP4.3 Patent Application Publication Jul. 7, 2011 Sheet 24 of 84 US 2011/O166063 A1 plcohol Figure BIP5.1 Patent Application Publication Jul. 7, 2011 Sheet 25 of 84 US 2011/O166063 A1 (SBC-30K)-biphalin Free PEG/(SBC-30K)-biphalin Figure BIP5.2 Patent Application Publication Jul. 7, 2011 Sheet 26 of 84 US 2011/O166063 A1 Opioid Receptor (Human Recombinant) Binding Assay 120 O Biphalin o Biphalin (72hG37°C) iss 100 Di-CAC-20K-biphalin 80 O Di-CAC-20K-biphalin (72hG37°C g 60 3. Z 40 E 20 10-10 10-9 10-8 10-7 10-6 10-5 10-4 log inhibitor (M) Ligand): 5.0 nM Kid: 4.0 nM & Opioid Receptor (Human Recombinant) Binding Assay 120 Biphalin 100 Biphalin (72hQ37°C) Di-CAC-20K-biphalin 80 D-CAC-2OK-biphalin (72hG37°C) 60 40 20 H-H--- O 10-10 10-9 10-8 107 10-6 10-5 104 Log Inhibitor (M) (Ligand): 5.0 nM Ko: 3.9 nM Figure BIP6.1 Patent Application Publication Jul.
Load more

Recommended publications
  • Amylase Release from Rat Parotid Gland Slices C.L
    Br. J. P!harmnic. (1981) 73, 517-523 THE EFFECTS OF SUBSTANCE P AND RELATED PEPTIDES ON a- AMYLASE RELEASE FROM RAT PAROTID GLAND SLICES C.L. BROWN & M.R. HANLEY MRC Neurochemical Pharmacology Unit, Medical Research Council Centre, Medical School, Hills Road, Cambridge CB2 2QH 1 The effects of substance P and related peptides on amylase release from rat parotid gland slices have been investigated. 2 Supramaximal concentrations (1 F.M) of substance P caused enhancement of amylase release over the basal level within 1 min; this lasted for at least 40 min at 30°C. 3 Substance P-stimulated amylase release was partially dependent on extracellular calcium and could be inhibited by 50% upon removal of extracellular calcium. 4 Substance P stimulated amylase release in a dose-dependent manner with an ED50 of 18 nm. 5 All C-terminal fragments of substance P were less potent than substance P in stimulating amylase release. The C-terminal hexapeptide of substance P was the minimum structure for potent activity in this system, having 1/3 to 1/8 the potency of substance P. There was a dramatic drop in potency for the C-terminal pentapeptide of substance P or substance P free acid. Physalaemin was more potent than substance P (ED50 = 7 nM), eledoisin was about equipotent with substance P (ED5o = 17 nM), and kassinin less potent than substance P (ED50 = 150 nM). 6 The structure-activity profile observed is very similar to that for stimulation of salivation in vivo, indicating that the same receptors are involved in mediating these responses.
    [Show full text]
  • Evaluation of in Silico Approach for Prediction of Presence of Opioid Peptides in Wheat
    Evaluation of in silico approach for prediction of presence of opioid peptides in wheat This is the Accepted version of the following publication Garg, Swati, Apostolopoulos, Vasso, Nurgali, Kulmira and Mishra, Vijay Kumar (2018) Evaluation of in silico approach for prediction of presence of opioid peptides in wheat. Journal of Functional Foods, 41. 34 - 40. ISSN 1756-4646 The publisher’s official version can be found at https://www.sciencedirect.com/science/article/pii/S1756464617307454 Note that access to this version may require subscription. Downloaded from VU Research Repository https://vuir.vu.edu.au/36577/ 1 1 Evaluation of in silico approach for prediction of presence of opioid peptides in wheat 2 gluten 3 Abstract 4 Opioid like morphine and codeine are used for the management of pain, but are associated 5 with serious side-effects limiting their use. Wheat gluten proteins were assessed for the 6 presence of opioid peptides on the basis of tyrosine and proline within their sequence. Eleven 7 peptides were identified and occurrence of predicted sequences or their structural motifs were 8 analysed using BIOPEP database and ranked using PeptideRanker. Based on higher peptide 9 ranking, three sequences YPG, YYPG and YIPP were selected for determination of opioid 10 activity by cAMP assay against µ and κ opioid receptors. Three peptides inhibited the 11 production of cAMP to varied degree with EC50 values of YPG, YYPG and YIPP were 5.3 12 mM, 1.5 mM and 2.9 mM for µ-opioid receptor, and 1.9 mM, 1.2 mM and 3.2 mM for κ- 13 opioid receptor, respectively.
    [Show full text]
  • N-Arachidonoyl Dopamine Modulates Acute Systemic Inflammation Via Nonhematopoietic TRPV1
    N-Arachidonoyl Dopamine Modulates Acute Systemic Inflammation via Nonhematopoietic TRPV1 This information is current as Samira K. Lawton, Fengyun Xu, Alphonso Tran, Erika of October 1, 2021. Wong, Arun Prakash, Mark Schumacher, Judith Hellman and Kevin Wilhelmsen J Immunol 2017; 199:1465-1475; Prepublished online 12 July 2017; doi: 10.4049/jimmunol.1602151 http://www.jimmunol.org/content/199/4/1465 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2017/07/12/jimmunol.160215 Material 1.DCSupplemental http://www.jimmunol.org/ References This article cites 69 articles, 11 of which you can access for free at: http://www.jimmunol.org/content/199/4/1465.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on October 1, 2021 • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Author Choice Freely available online through The Journal of Immunology Author Choice option Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2017 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology N-Arachidonoyl Dopamine Modulates Acute Systemic Inflammation via Nonhematopoietic TRPV1 Samira K.
    [Show full text]
  • The Action Mechanism of Daptomycin
    The final publication is available at Elsevier via http://dx.doi.org/10.1016/j.bmc.2016.05.052 © 2016. The Action Mechanism of Daptomycin Scott D. Taylor, Michael Palmer Department of Chemistry, University of Waterloo, Waterloo, ON N2L 3G1, Canada Abstract Daptomycin is a lipopeptide antibiotic produced by the soil bacterium Strep- tomyces roseosporus that is clinically used to treat severe infections with Gram- positive bacteria. In this review, we discuss the mode of action of this impor- tant antibiotic. Although daptomycin is structurally related to amphomycin and similar lipopeptides that inhibit peptidoglycan biosynthesis, experimen- tal studies have not produced clear evidence that daptomycin shares their action mechanism. Instead, the best characterized effect of daptomycin is the permeabilization and depolarization of the bacterial cell membrane. This ac- tivity, which can account for daptomycin’s bactericidal effect, correlates with the level of phosphatidylglycerol (PG) in the membrane. Accordingly, reduced synthesis of PG or its increased conversion to lysyl-PG promotes bacterial re- sistance to daptomycin. While other resistance mechanisms suggest that dap- tomycin may indeed directly interfere with cell wall synthesis or cell division, such effects still await direct experimental confirmation. Daptomycin’s com- plex structure and biosynthesis have hampered the analysis of its structure activity relationships. Novel methods of total synthesis, including a recent one that is carried out entirely on a solid phase, will enable a more thorough and systematic exploration of the sequence space. Keywords: calcium-dependent lipopeptide antibiotics, bacterial membranes, membrane potential Email addresses: [email protected] (Scott D. Taylor), [email protected] (Michael Palmer) Preprint submitted to Bioorganic & Medicinal Chemistry May 6, 2016 1.
    [Show full text]
  • Vancomycin-Lipopeptide Conjugates with High Antimicrobial Activity on Vancomycin-Resistant Enterococci
    pharmaceuticals Article Vancomycin-Lipopeptide Conjugates with High Antimicrobial Activity on Vancomycin-Resistant Enterococci 1, 1, 2 3 3 Eric Mühlberg y, Florian Umstätter y, Cornelius Domhan , Tobias Hertlein , Knut Ohlsen , Andreas Krause 1, Christian Kleist 1, Barbro Beijer 1, Stefan Zimmermann 4, Uwe Haberkorn 1,5, Walter Mier 1 and Philipp Uhl 1,* 1 Department of Nuclear Medicine, Heidelberg University Hospital, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany; [email protected] (E.M.); [email protected] (F.U.); [email protected] (A.K.); [email protected] (C.K.); [email protected] (B.B.); [email protected] (U.H.); [email protected] (W.M.) 2 Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, Im Neuenheimer Feld 364, 69120 Heidelberg, Germany; [email protected] 3 Institute for Molecular Infection Biology, University of Würzburg, Josef-Schneider-Straße 2/D15, 97080 Würzburg, Germany; [email protected] (T.H.); [email protected] (K.O.) 4 Department of Medical Microbiology and Hygiene, Heidelberg University Hospital, Im Neuenheimer Feld 324, 69120 Heidelberg Germany; [email protected] 5 Clinical Cooperation Unit Nuclear Medicine, German Cancer Research Centre (DKFZ), Im Neuenheimer Feld 260, 69120 Heidelberg, Germany * Correspondence: [email protected]; Tel.: +49-6221-56-7726 These authors contributed equally. y Received: 23 April 2020; Accepted: 27 May 2020; Published: 29 May 2020 Abstract: Multidrug-resistant bacteria represent one of the most important health care problems worldwide. While there are numerous drugs available for standard therapy, there are only a few compounds capable of serving as a last resort for severe infections.
    [Show full text]
  • Intracerebroventricular Responses to Neuropeptide Y in the Antagonists
    British Journal of Pharmacology (1996) 117, 241-249 B 1996 Stockton Press All rights reserved 0007-1188/96 $12.00 9 Intracerebroventricular responses to neuropeptide y in the conscious rat: characterization of its receptor with selective antagonists Pierre Picard & 'Rejean Couture Department of Physiology, Faculty of Medicine, Universite de Montreal, C.P. 6128, Succursale Centre-Ville, Montreal, Quebec, Canada H3C 3J7 1 The cardiovascular and behavioural effects elicited by the intracerebroventricular (i.c.v.) administration of neuropeptide y (NPy) in the conscious rat were assessed before and 5 min after i.c.v. pretreatment with antagonists selective for NKI (RP 67,580), NK2 (SR 48,968) and NK3 (R 820) receptors. In addition, the central effects of NPy before and after desensitization of the NK, and NK2 receptors with high doses of substance P (SP) and neurokinin A (NKA) were compared. 2 Intracerebroventricular injection of NPy (10-780 pmol) evoked dose- and time-dependent increases in mean arterial blood pressure (MAP), heart rate (HR), face washing, head scratching, grooming and wet-dog shake behaviours. Similar injection of vehicle or 1 pmol NPy had no significant effect on those parameters. 3 The cardiovascular and behavioural responses elicited by NPy (25 pmol) were significantly and dose- dependently reduced by pretreatment with 650 pmol and 6.5 nmol of SR 48,968. No inhibition of NPy responses was observed when 6.5 nmol of RP 67,580 was used in a similar study. Moreover, the prior co-administration of SR 48,968 (6.5 nmol) and RP 67,580 (6.5 nmol) with or without R 820 (6.5 nmol) did not reduce further the central effects of NPy and significant residual responses (30-50%) remained.
    [Show full text]
  • Cell Penetrating Peptides, Novel Vectors for Gene Therapy
    pharmaceutics Review Cell Penetrating Peptides, Novel Vectors for Gene Therapy Rebecca E. Taylor 1 and Maliha Zahid 2,* 1 Mechanical Engineering, Biomedical Engineering and Electrical and Computer Engineering, Carnegie Mellon University, Pittsburgh, PA 15213, USA; [email protected] 2 Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15201, USA * Correspondence: [email protected]; Tel.: +1-412-692-8893; Fax: +1-412-692-6184 Received: 5 February 2020; Accepted: 1 March 2020; Published: 3 March 2020 Abstract: Cell penetrating peptides (CPPs), also known as protein transduction domains (PTDs), first identified ~25 years ago, are small, 6–30 amino acid long, synthetic, or naturally occurring peptides, able to carry variety of cargoes across the cellular membranes in an intact, functional form. Since their initial description and characterization, the field of cell penetrating peptides as vectors has exploded. The cargoes they can deliver range from other small peptides, full-length proteins, nucleic acids including RNA and DNA, liposomes, nanoparticles, and viral particles as well as radioisotopes and other fluorescent probes for imaging purposes. In this review, we will focus briefly on their history, classification system, and mechanism of transduction followed by a summary of the existing literature on use of CPPs as gene delivery vectors either in the form of modified viruses, plasmid DNA, small interfering RNA, oligonucleotides, full-length genes, DNA origami or peptide nucleic acids. Keywords: cell penetrating peptides; protein transduction domains; gene therapy; small interfering RNA 1. Introduction The plasma membrane of a cell is essential to its identity and survival, but at the same time presents a barrier to intracellular delivery of potentially diagnostic or therapeutic cargoes.
    [Show full text]
  • Fungal Pathogenesis in Humans the Growing Threat
    Fungal Pathogenesis in Humans The Growing Threat Edited by Fernando Leal Printed Edition of the Special Issue Published in Genes www.mdpi.com/journal/genes Fungal Pathogenesis in Humans Fungal Pathogenesis in Humans The Growing Threat Special Issue Editor Fernando Leal MDPI • Basel • Beijing • Wuhan • Barcelona • Belgrade Special Issue Editor Fernando Leal Instituto de Biolog´ıa Funcional y Genomica/Universidad´ de Salamanca Spain Editorial Office MDPI St. Alban-Anlage 66 4052 Basel, Switzerland This is a reprint of articles from the Special Issue published online in the open access journal Genes (ISSN 2073-4425) from 2018 to 2019 (available at: https://www.mdpi.com/journal/genes/special issues/Fungal Pathogenesis Humans Growing Threat). For citation purposes, cite each article independently as indicated on the article page online and as indicated below: LastName, A.A.; LastName, B.B.; LastName, C.C. Article Title. Journal Name Year, Article Number, Page Range. ISBN 978-3-03897-900-5 (Pbk) ISBN 978-3-03897-901-2 (PDF) Cover image courtesy of Fernando Leal. c 2019 by the authors. Articles in this book are Open Access and distributed under the Creative Commons Attribution (CC BY) license, which allows users to download, copy and build upon published articles, as long as the author and publisher are properly credited, which ensures maximum dissemination and a wider impact of our publications. The book as a whole is distributed by MDPI under the terms and conditions of the Creative Commons license CC BY-NC-ND. Contents About the Special Issue Editor ...................................... vii Fernando Leal Special Issue: Fungal Pathogenesis in Humans: The Growing Threat Reprinted from: Genes 2019, 10, 136, doi:10.3390/genes10020136 ..................
    [Show full text]
  • NIDA Drug Supply Program Catalog, 25Th Edition
    RESEARCH RESOURCES DRUG SUPPLY PROGRAM CATALOG 25TH EDITION MAY 2016 CHEMISTRY AND PHARMACEUTICS BRANCH DIVISION OF THERAPEUTICS AND MEDICAL CONSEQUENCES NATIONAL INSTITUTE ON DRUG ABUSE NATIONAL INSTITUTES OF HEALTH DEPARTMENT OF HEALTH AND HUMAN SERVICES 6001 EXECUTIVE BOULEVARD ROCKVILLE, MARYLAND 20852 160524 On the cover: CPK rendering of nalfurafine. TABLE OF CONTENTS A. Introduction ................................................................................................1 B. NIDA Drug Supply Program (DSP) Ordering Guidelines ..........................3 C. Drug Request Checklist .............................................................................8 D. Sample DEA Order Form 222 ....................................................................9 E. Supply & Analysis of Standard Solutions of Δ9-THC ..............................10 F. Alternate Sources for Peptides ...............................................................11 G. Instructions for Analytical Services .........................................................12 H. X-Ray Diffraction Analysis of Compounds .............................................13 I. Nicotine Research Cigarettes Drug Supply Program .............................16 J. Ordering Guidelines for Nicotine Research Cigarettes (NRCs)..............18 K. Ordering Guidelines for Marijuana and Marijuana Cigarettes ................21 L. Important Addresses, Telephone & Fax Numbers ..................................24 M. Available Drugs, Compounds, and Dosage Forms ..............................25
    [Show full text]
  • Back Matter (PDF)
    MOLECULAR PHARMACOLOGY 26:605-609 AUTHOR INDEX FOR VOLUME 26 A berg, Aaron, Watanabe, Kyoichi A., Fox, Jack J., and Philips, Frederick S. Metabolic Competition Studies of 2’-Fluoro-S-iodo-l- Albengres, Edith. See Urien, Riant, Brioude, and Tillement, 322 f3-D-arabinofuranosylcytosine in Vero Cells and Herpes Simplex Albuquerque, E. X. See Aracava, Ikeda, Daly, and Brooks, 304 Type 1-Infected Vero Cells, 587 See Ikeda, Aronstam, Daly, and Aracava, 293 Christie, Nelwyn T. See Cantoni, Swann, Drath, and Costa, 360 Ambler, S. Kelly, Brown, R. Dale, and Taylor, Palmer. The Chrivia, John. See Bolger, Dionne, Johnson, and Taylor, 57 Relationship between Phosphatidylinositol Metabolism and Mobili- Colacino, Joseph M. See Chou, Lopez, Feinberg, Watanabe, Fox, and zation of Intracellular Calcium Elicited by Alpha,-Adrenergic Recep- Philips, 587 tar Stimulation in BC3H-1 Muscle Cells, 405 Collins, Sheila, and Marletta, Michael A. Carcinogen-Binding Aracava, Y. Ikeda, S. R., Daly, J. W., Brookes, N., and Albu- Proteins: High-Affinity Binding Sites for Benzo[ajpyrene in Mouse querque, E. X. Interactions of Bupivacaine with Ionic Channels of Liver Distinct from the Ah Receptor, 353 the Nicotonic Receptor: Analysis of Single-Channel Currents, 304 Cooper, Dermot M. F. See Sadler and Mailer, 526 See Ikeda, Aronstam, Daly, and Albuquerque, 293 Corbett, Michael D. See Doerge, 348 Aronstam, R. S. See Ikeda, S. R. , Daly, J. W., Aracava, Y. , and Cormier, Ethel. See Jordan, Lieberman, Koch, Bagley, and Ruenitz, Albuquerque, E. X. , 293 272 Aub, Debra L. See Putney, McKinney, and Leslie, 261 Costa, Erminio. See Quach, Tang, Kageyama, Mocchetti, Guidotti, Meek, and Schwartz, 255 B Costa, Max.
    [Show full text]
  • Modulation of Opioid Transport at the Blood-Brain Barrier by Altered ATP-Binding Cassette (ABC) Transporter Expression and Activity
    pharmaceutics Review Modulation of Opioid Transport at the Blood-Brain Barrier by Altered ATP-Binding Cassette (ABC) Transporter Expression and Activity Junzhi Yang 1, Bianca G. Reilly 2, Thomas P. Davis 1,2 and Patrick T. Ronaldson 1,2,* 1 Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, 1295 N. Martin St., P.O. Box 210207, Tucson, AZ 85721, USA; [email protected] (J.Y.); [email protected] (T.P.D.) 2 Department of Pharmacology, College of Medicine, University of Arizona, 1501 N. Campbell Ave, P.O. Box 245050, Tucson, AZ 85724-5050, USA; [email protected] * Correspondence: [email protected]; Tel.: +1-520-626-2173 Received: 19 September 2018; Accepted: 16 October 2018; Published: 18 October 2018 Abstract: Opioids are highly effective analgesics that have a serious potential for adverse drug reactions and for development of addiction and tolerance. Since the use of opioids has escalated in recent years, it is increasingly important to understand biological mechanisms that can increase the probability of opioid-associated adverse events occurring in patient populations. This is emphasized by the current opioid epidemic in the United States where opioid analgesics are frequently abused and misused. It has been established that the effectiveness of opioids is maximized when these drugs readily access opioid receptors in the central nervous system (CNS). Indeed, opioid delivery to the brain is significantly influenced by the blood-brain barrier (BBB). In particular, ATP-binding cassette (ABC) transporters that are endogenously expressed at the BBB are critical determinants of CNS opioid penetration. In this review, we will discuss current knowledge on the transport of opioid analgesic drugs by ABC transporters at the BBB.
    [Show full text]
  • Opioid Peptides in Peripheral Pain Control
    Review Acta Neurobiol Exp 2011, 71: 129–138 Opioid peptides in peripheral pain control Anna Lesniak*, Andrzej W. Lipkowski Mossakowski Medical Research Centre Polish Academy of Sciences, Warsaw; *Email: [email protected] Opioids have a long history of therapeutic use as a remedy for various pain states ranging from mild acute nociceptive pain to unbearable chronic advanced or end-stage disease pain. Analgesia produced by classical opioids is mediated extensively by binding to opioid receptors located in the brain or the spinal cord. Nevertheless, opioid receptors are also expressed outside the CNS in the periphery and may become valuable assets in eliciting analgesia devoid of shortcomings typical for the activation of their central counterparts. The discovery of endogenous opioid peptides that participate in the formation, transmission, modulation and perception of pain signals offers numerous opportunities for the development of new analgesics. Novel peptidic opioid receptor analogs, which show limited access through the blood brain barrier may support pain therapy requiring prolonged use of opioid drugs. Key words: immune cells, opioid peptides, pain, peripheral analgesia Abbreviations: β-FNA - β-funaltrexamine, BBB - blood-brain-barrier, CGRP - calcitonin gene-related peptide, CFA - complete Freund adjuvant, CNS - central nervous system, CRF - corticotropin releasing factor, CYP - cyprodime, DAGO - [Tyr-D-Ala- Gly-Me-Phe-Gly-ol]-enkephalin, DAMGO - [D-Ala2, N-MePhe4, Gly-ol]-enkephalin, DOR - delta opioid receptor, DPDPE - [D-Pen2,5]-enkephalin, DRG - dorsal root ganglion, EM-1 - endomorphin 1, EM-2 - endomorphin 2, KOR - kappa opioid receptor, MOR - mu opioid receptor, NLZ – naloxonazine, NTI - naltrindole, NLXM - naloxone methiodide; nor-BNI – nor-binaltorphimine, PDYN - prodynorphin, PENK - proenkephalin, PNS - peripheral nervous system, POMC - proopiomelanocortin INTRODUCTION ic pain.
    [Show full text]