Prodrugs of Peptides IV: Bioreversible Derivatization of the Pyroglutamyl Group by N-Acylation and N-Aminomethylation to Effect Protection against Pyroglutamyl Aminopeptidase

Bundgaard, Hans; Møss, Judi

doi:10.1002/jps.2600780210

Cited by 23 publications

(7 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Modification of the N-terminus with acyl moieties has been shown to increase stability and thus provide a means of prolonging the duration of action of the parent peptide. 22,[46][47][48] Introduction of a hydrophobic acyl group is also an effective means of increasing lipophilicity and thus may enhance peptide interactions with cellular membranes and penetration across biological barriers. 46,47,[49][50][51] Previously, it has been demonstrated that fatty acid conjugation with an R-MSH analogue can increase the biological activity of the peptide.…”

Section: Discussionmentioning

confidence: 99%

“…22,[46][47][48] Introduction of a hydrophobic acyl group is also an effective means of increasing lipophilicity and thus may enhance peptide interactions with cellular membranes and penetration across biological barriers. 46,47,[49][50][51] Previously, it has been demonstrated that fatty acid conjugation with an R-MSH analogue can increase the biological activity of the peptide. 22 Our laboratory and others [30][31][32] have reported studies aimed at improving the potency and selectivity of the melanocortin His-DPhe-Arg-Trp-NH 2 tetrapeptide agonist.…”

Section: Discussionmentioning

confidence: 99%

“…22,29,49 This hypothesis remains unchallenged, considering that both lipophilic character and membrane association can be enhanced by addition of hydrophobic groups to various peptides and proteins. 46,47,50,54,55 One can imagine that a covalently linked fatty acid may anchor to the cellular membrane, which might serve to concentrate the peptide juxtaposed to the membrane-embedded GPCR in a conformation suited for ligand-receptor interactions (Figure 7). 56 Sargent and Schwyzer proposed a model of membranemediated peptide receptor interactions in which the cellular membrane functions as a catalyst to enhance the rate of peptide association with the receptor.…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

N-Terminal Fatty Acylated His-dPhe-Arg-Trp-NH₂Tetrapeptides: Influence of Fatty Acid Chain Length on Potency and Selectivity at the Mouse Melanocortin Receptors and Human Melanocytes

et al. 2005

View full text Add to dashboard Cite

The melanocortin system is involved in the regulation of a diverse number of physiologically important pathways including pigmentation, feeding behavior, weight and energy homeostasis, inflammation, and sexual function. All the endogenous melanocortin agonist ligands possess the conserved His-Phe-Arg-Trp tetrapeptide sequence that is postulated to be important for melanocortin receptor molecular recognition and stimulation. Previous studies by our laboratory resulted in the discovery that increasing alkyl chain length at the N-terminal "capping" region of the His-dPhe-Arg-Trp-NH(2) tetrapeptide resulted in a 100-fold increased melanocortin receptor agonist potency. This study was undertaken to systematically evaluate the pharmacological effects of increasing N-capping alkyl chain length of the CH(3)(CH(2))(n)CO-His-dPhe-Arg-Trp-NH(2) (n = 6-16) tetrapeptide template. Twelve analogues were synthesized and pharmacologically characterized at the mouse melanocortin receptors MC1R and MC3R-MC5R and human melanocytes known to express the MC1R. These peptides demonstrated melanocortin receptor selectivity profiles different from those of previously published tetrapeptides. The most notable results of enhanced ligand potency (20- to 200-fold) and receptor selectivity were observed at the MC1R. Tetrapeptides that possessed greater than nine alkyl groups were superior to alpha-MSH in terms of the stimulation of human melanocyte tyrosinase activity. Additionally, the n-pentadecanoyl derivative had a residual effect on tyrosinase activity that existed for at least 4 days after the peptide was removed from the human melanocyte culture medium. These data demonstrate the utility, potency, and residual effect of melanocortin tetrapeptides by adding N-terminal fatty acid moieties.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

N-Terminal Fatty Acylated His-dPhe-Arg-Trp-NH₂Tetrapeptides: Influence of Fatty Acid Chain Length on Potency and Selectivity at the Mouse Melanocortin Receptors and Human Melanocytes

et al. 2005

View full text Add to dashboard Cite

show abstract

“…Thus, the protection of the pyroglutamyl residue of peptides from attack by pyrase may improve the delivery of such peptides in therapeutics. 91 Pyroglutamyl derivatives of several anticancer drugs have been proposed as potential prodrugs, designed to be cleaved in situ to the pharmacologically active cytotoxic agent in the presence of pyrase. 91 For targeting the tumor site, a pyrase chemically linked to a monoclonal antibody may be useful.…”

Section: A Proteases Of the C10 C11 And C15 Familiesmentioning

confidence: 99%

Bacterial protease inhibitors

Supuran

Scozzafava

Clare

2002

Medicinal Research Reviews

149

120

View full text Add to dashboard Cite

Serine-, cysteine-, and metalloproteases are widely spread in many pathogenic bacteria, where they play critical functions related to colonization and evasion of host immune defenses, acquisition of nutrients for growth and proliferation, facilitation of dissemination, or tissue damage during infection. Since all the antibiotics used clinically at the moment share a common mechanism of action, acting as inhibitors of the bacterial cell wall biosynthesis or affecting protein synthesis on ribosomes, resistance to these pharmacological agents represents a serious medical problem, which might be resolved by using new generation of antibiotics, possessing a different mechanism of action. Bacterial protease inhibitors constitute an interesting such possibility, due to the fact that many specific as well as ubiquitous proteases have recently been characterized in some detail in both gram-positive as well as gram-negative pathogens. Few potent, specific inhibitors for such bacterial proteases have been reported at this moment except for some signal peptidase, clostripain, Clostridium histolyticum collagenase, botulinum neurotoxin, and tetanus neurotoxin inhibitors. No inhibitors of the critically important and ubiquitous AAA proteases, degP or sortase have been reported, although such compounds would presumably constitute a new class of highly effective antibiotics. This review presents the state of the art in the design of such enzyme inhibitors with potential therapeutic applications, as well as recent advances in the use of some of these proteases in therapy.

show abstract

“…Despite advancements in orthopedic surgical techniques, critical care medicine and multidisciplinary interventions, pelvic and acetabular fractures (PAF) remain complex injuries with relatively high morbidity and mortality [1][2][3][4]. One-year mortality ranges from 5 to 42%, with patient age, blood transfusions, Injury Severity Score, pelvic instability and open injury serving as important prognostic factors [5,6].…”

Section: Introductionmentioning

confidence: 99%

Perioperative management of acetabular and pelvic fractures: evidence-based recommendations

Yakkanti

Mohile

Cohen-Levy

et al. 2021

Arch Orthop Trauma Surg

View full text Add to dashboard Cite

Purpose The American Academy of Orthopaedic Surgeons does not currently provide clinical practice guidelines for management of PAF. Accordingly, this article aims to review and consolidate the relevant historical and recent literature in important topics pertaining to perioperative management of PAF. Methods A thorough literature review using PubMed, Cochrane and Embase databases was performed to assess preoperative, intraoperative and postoperative management of PAF fracture. Topics reviewed included: time from injury to definitive fixation, the role of inferior vena cava filters (IVCF), tranexamic acid (TXA) use, intraopoperative cell salvage, incisional negative pressure wound therapy (NPWT), intraoperative antibiotic powder use, heterotopic ossification prophylaxis, and pre-and postoperative venous thromboembolism (VTE) prophylaxis. Results A total of 126 articles pertaining to the preoperative, intraoperative and postoperative management of PAF were reviewed. Articles reviewed by topic include 13 articles pertaining to time to fixation, 23 on IVCF use, 14 on VTE prophylaxis, 20 on TXA use, 10 on cell salvage, 10 on iNPWT 14 on intraoperative antibiotic powder and 20 on HO prophylaxis. An additional eight articles were reviewed to describe background information. Five articles provided information for two or more treatment modalities and were therefore included in multiple categories when tabulating the number of articles reviewed per topic. ConclusionThe literature supports the use of radiation therapy for HO prophylaxis, early (< 5 days from injury) surgical intervention and the routine use of intraoperative TXA. The literature does not support the routine use of iNPWT or IVCF. There is inadequate information to make a recommendation regarding the use of cell salvage and wound infiltration with antibiotic powder. While the routine use of chemical VTE prophylaxis is recommended, there is insufficient evidence to recommend the optimal agent and duration of therapy.

show abstract

Prodrugs of Peptides IV: Bioreversible Derivatization of the Pyroglutamyl Group by N-Acylation and N-Aminomethylation to Effect Protection against Pyroglutamyl Aminopeptidase

Cited by 23 publications

References 36 publications

N-Terminal Fatty Acylated His-dPhe-Arg-Trp-NH₂Tetrapeptides: Influence of Fatty Acid Chain Length on Potency and Selectivity at the Mouse Melanocortin Receptors and Human Melanocytes

N-Terminal Fatty Acylated His-dPhe-Arg-Trp-NH₂Tetrapeptides: Influence of Fatty Acid Chain Length on Potency and Selectivity at the Mouse Melanocortin Receptors and Human Melanocytes

Bacterial protease inhibitors

Perioperative management of acetabular and pelvic fractures: evidence-based recommendations

Contact Info

Product

Resources

About

Prodrugs of Peptides IV: Bioreversible Derivatization of the Pyroglutamyl Group by N-Acylation and N-Aminomethylation to Effect Protection against Pyroglutamyl Aminopeptidase

Cited by 23 publications

References 36 publications

N-Terminal Fatty Acylated His-dPhe-Arg-Trp-NH2Tetrapeptides: Influence of Fatty Acid Chain Length on Potency and Selectivity at the Mouse Melanocortin Receptors and Human Melanocytes

N-Terminal Fatty Acylated His-dPhe-Arg-Trp-NH2Tetrapeptides: Influence of Fatty Acid Chain Length on Potency and Selectivity at the Mouse Melanocortin Receptors and Human Melanocytes

Bacterial protease inhibitors

Perioperative management of acetabular and pelvic fractures: evidence-based recommendations

Contact Info

Product

Resources

About

N-Terminal Fatty Acylated His-dPhe-Arg-Trp-NH₂Tetrapeptides: Influence of Fatty Acid Chain Length on Potency and Selectivity at the Mouse Melanocortin Receptors and Human Melanocytes

N-Terminal Fatty Acylated His-dPhe-Arg-Trp-NH₂Tetrapeptides: Influence of Fatty Acid Chain Length on Potency and Selectivity at the Mouse Melanocortin Receptors and Human Melanocytes