Prodrugs to enhance central nervous system effects of the TRH-like peptide pGlu-Glu-Pro-NH2

Prókai-Tátrai, Katalin; Nguyen, Vien; Zharikova, Alevtina D.; Braddy, April C.; Stevens, Stanley M.; Prókai, László

doi:10.1016/s0960-894x(03)00081-7

Cited by 26 publications

(32 citation statements)

References 21 publications

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“…After cleaving from the resin with 95:2.5:2.5 trifluoroacetic acid/water/triisopropylsilane (v/v/v), the crude peptides were purified by semipreparative reversedphase HPLC using an octadecylsilica column (13,14). All other peptides were custom synthesized on 2-3-mg scale by Synthetic Biomolecules (San Diego, CA).…”

Section: Methodsmentioning

confidence: 99%

Factors That Contribute to the Misidentification of Tyrosine Nitration by Shotgun Proteomics

Stevens

Prókai-Tátrai

Prókai

2008

Molecular & Cellular Proteomics

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The high selectivity and throughput of tandem mass spectrometry allow for rapid identification and localization of various posttranslational protein modifications from complex mixtures by shotgun approaches. Although sequence database search algorithms provide necessary support to process the potentially enormous quantity of MS/MS spectra generated from large scale tandem mass spectrometry experiments, false positive identifications of peptide modifications may exist even after implementation of stringent identification criteria. In this report, we describe factors that lead to misinterpretation of MS/MS spectra as well as common chemical and experimental artifacts that generate false positives using the proteomics-based identification of tyrosine nitration as an example. In addition to the proposed manual validation criteria, the importance of peptide synthesis and subsequent MS/MS characterization for validation of peptide nitration demonstrated by several examples from earlier publications is also presented. Molecular & Cellular Proteomics 7:2442-2451, 2008.The advancement in mass spectrometric instrumentation has significantly enhanced proteomics-based research yet presents a new and somewhat difficult challenge in terms of data management and analysis (1-4). Current commercially available mass spectrometers can typically generate thousands of MS/MS spectra in a single HPLC-tandem MS experiment resulting in a large number of high confidence peptide identifications after database searching. Nevertheless numerous spectra remain mis-or unidentified because of a variety of factors such as poor spectral quality, nonspecific protein cleavage, and chemical or posttranslational modifications. For those peptide sequences that are identified from MS/MS spectra based on surpassing statistically significant scores established in various database search algorithms, a number of false positives can be present depending on the stringency of the identification criteria. Recent developments in database search strategies have offered new procedures for the assessment of false positive rates for peptide identification (5, 6); however, to provide a detailed survey of proteins obtained from complex biological samples, a compromise must be established to maximize the number of true positive identifications. Therefore, manual validation of MS/MS-based peptide identifications remains critical in this regard.The introduction of specific guidelines for reporting peptide and protein identifications (7) has greatly enhanced the quality of publications in the area of proteomics and has provided an essential foundation for the accurate expansion of discoverybased research. Although manual validation still plays a major role in the identification of proteins and their corresponding posttranslational modifications, few uniform guidelines exist to formulate acceptable manual validation criteria. The development of such guidelines is rather complex because a variety of factors can impact the approach used to manually validate MS/MS spectra in...

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Section: Methodsmentioning

confidence: 99%

Factors That Contribute to the Misidentification of Tyrosine Nitration by Shotgun Proteomics

Stevens

Prókai-Tátrai

Prókai

2008

Molecular & Cellular Proteomics

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“…, where t R(X) and t R(V) are the retention times for the compound of interest and the void volume marker [Glu 2 ]TRH [19], respectively. Detection was done by APCI-MS using the protonated molecules for the analytes and the void volume marker (m/z 363, 365, 391 and 355 for TRH, 1, 2 and [Glu 2 ]TRH, respectively) to retrieve selected-ion chromatograms and obtain t R values.…”

Section: Immobilized Artificial Membrane Chromatography (Iamc)mentioning

confidence: 99%

Exploratory neuropharmacological evaluation of a conformationally constrained thyrotropin-releasing hormone analogue

Teixidó¹,

Prókai-Tátrai²,

Wang³

et al. 2007

Brain Research Bulletin

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A conformationally constrained peptidomimetic derived from the endocrine and neuroactive tripeptide thyrotropin-releasing hormone (pGlu-His-Pro-NH 2 ) was synthesized by convenient solidphase organic chemistry and evaluated as a potential central nervous system agent. While this ethylene-bridged peptide analogue has been reported to lack the hormonal effect of the native peptide, we have shown in animal models that it possesses central nervous system activity characteristic of thyrotropin-releasing hormone. Compared to control, the peptidomimetic showed significant analeptic and antidepressant-like potencies. Moreover, an enhanced selectivity in antidepressant-like effect was measured when compared to that of the native peptide. Immobilized artificial membrane chromatography and in vitro metabolic stability studies also revealed that this constrained peptidomimetic has higher affinity to the blood-brain barrier than the native peptide and is metabolically stable. Consequently, this structure may be used as a template to design centrally selective and metabolically stable thyrotropin-releasing hormone analogues as potential neuropharmaceutical agents.

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“…The paracellular pathways (see below) in this vascular area are relatively restricted, yet the BBB endothelium is not all that impermeable and yet can be traversed via aplethora of agents (for reviews see [273,274]). From a biological standpoint, this can be illustrated by the fact that Escherichia coli invades the central nervous system by transmigration through brain microvascular EC using an actin-and microtubule-dependent phagocytic mechanism, although this pathway was inactive in systemic EC [275].…”

Section: Traversing Endothelial Barriers Via Transcytosis and Paracelmentioning

confidence: 99%

“…In particular, brain microvascular EC form an extremely dense monolayer, resulting in an extremely tight BBB, which lacks significant permeability for plasma proteins and possesses specific enzymatic systems (glycoprotein P, e.g.) to facilitate reverse transport of molecules from the brain tissue to the circulation * [274]. Clearly, due to these differences in vascular permeability, BBB endothelium represents the most formidable biological barrier for the extravascular drug delivery, while fenestrated endothelium does not restrict extravasation of even large carriers such as liposomes, polymer particles and viruses [278].…”

Section: Traversing Endothelial Barriers Via Transcytosis and Paracelmentioning

confidence: 99%

Targeting of Drugs to ICAM for Treatment of Acute Lung Injury

Muzykantov¹

2004

PsycEXTRA Dataset

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_ Public reporting burden for this coliection of information is estimated to average 1 tiour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining " the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing Uiis bunjen to Washington Headquarters Services, Directorate for Information Operations and Reports, 1215 Jefferson Davis Highv^ay, Suite 1204, Arlington, VA 22202-4302, and to the Office of Management and Budget, Papenrork Reduction Project (0704-0188), Washington, DC 20503 AGENCY USE ONLY (Leave blank) REPORT DATE April 2004 REPORT TYPE AND DATES COVERED Annual (11 Mar 2003 -10 Mar 2004) TITLE AND SUBTITLE Targeting of Drugs to ICAM for Treatment of Acute Lung Injury AUTHOR(S)Vladimir Muzykantov, Ph.D. FUNDING NUMBERS DAMD17-02-1-0197 PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES)University of Pennsylvania Philadelphia, PA 19104-6205 E-Mail: muzykantOmail. med. upenn. edu PERFORMING ORGANIZATION REPORT NUMBER SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) U.S. Army Medical Research and Materiel Command Fort Detrick, Maryland 21702-5012 SPONSORING / MONITORING AGENCY REPORT NUMBER SUPPLEMENTARY NOTESOriginal contains color plates: ALL DTIC reproductions will be in black and white 12a. DISTRIBUTION / AVAILABILITY STATEMENT Approved for Public Release; Distribution Unlimited 12b. DISTRIBUTION CODE ABSTRACT (Maximum 200 Words)In the second year, we characterized intracellular traffic and final destination of anti-CAM conjugates in endothelial cells (EC) and found that CAM-mediated endocytosis initiates an unusually slow vesicular traffic that delivers conjugates to lysosomes several hours after internalization. Further, auxiliary drugs that regulate these processes can be utilized for prolongation of therapeutic duration of internalized conjugates. We characterized a series of in-house models of human ALI (injection of anti-TM/GOX and hyperoxia in mice), studied dynamics and role of EC cell adhesion molecules and leukocytes in these models and developed a new, clinically relevant and reliable model of ALI, based on combined treatment with anti-TM/GOX and hyperoxia. We synthesized anti-CAM/SOD conjugate with proper targeting size (~200 nm), enzymatic activity and affinity to EC and documented that it accumulates in the pulmonary vasculature after intravenous injection, thus satisfying main requirements for subsequent testing in animal models of ALI. In vitro and in vivo fibrinolysis studies have been employed in order to select the optimal candidate fibrinolytic (a novel tPA derivative, Tenektase) for targeting to endothelial CAM. Design and production of optimized affinity carriers for this purpose is in progress. SUBJECT TERMSEndothelium, immunotargeting, oxidant stress, thrombosis, ICAM-1 Vladimir Muzykantov, PI, DAMD 17-02-1-0197 "ICAM Targeting in Acute Lung Injury" Second Annual ...

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Prodrugs to enhance central nervous system effects of the TRH-like peptide pGlu-Glu-Pro-NH2

Cited by 26 publications

References 21 publications

Factors That Contribute to the Misidentification of Tyrosine Nitration by Shotgun Proteomics

Factors That Contribute to the Misidentification of Tyrosine Nitration by Shotgun Proteomics

Exploratory neuropharmacological evaluation of a conformationally constrained thyrotropin-releasing hormone analogue

Targeting of Drugs to ICAM for Treatment of Acute Lung Injury

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