Improvement of oral peptide bioavailability: Peptidomimetics and prodrug strategies

Pauletti, Giovanni M.; Gangwar, Sanjeev; Siahaan, Teruna J.; Aubé, Jeffrey; Borchardt, Ronald T.

doi:10.1016/s0169-409x(97)00045-8

Cited by 196 publications

(124 citation statements)

References 160 publications

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“…Their metabolic stability, permeability, and thus longer degrading time make these peptidomimetic compounds prospective candidates for drug development. 17 Therapeutic applications require a microscopic-level understanding of these mimetics, which can be achieved using density functional theory (DFT) methods. This work focuses on tracing the electronic structure, excitation properties, and hole-migration dynamics for a few experimentally realized UP models using computational tools.…”

Section: ■ Introductionmentioning

confidence: 99%

Computational Studies on Structural, Excitation, and Charge-Transfer Properties of Ureidopeptidomimetics

2016

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Peptides with ureido group enclosing backbones are considered peptidomimetics and are known for their higher stabilities, biocompatibilities, antibiotic, inhibitor, and charge-transduction activities. These peptidomimetics have some unique applications, which are quite different from those of natural peptides. Hence, it is imperative to appreciate their properties at a microscopic level. In this regard, this work outlines, in detail, the charge transfer (CT) properties, holemigration dynamics, and electronic structures of various experimentally comprehended ureidopeptidomimetic models using density functional theory (DFT). Time-dependent DFT and complete active space self-consistent field computations on basic models provide the necessary evidence for the viability of CT from the end enfolding the ureido group to the other end with a carboxylate entity. This donor-to-acceptor CT has been reflected in excitation studies, in which the higher intensity band corresponds to CT from the π orbital of the ureido group to the π* orbital of the carboxylate entity. Further, hole-migration studies have shown that charge can evolve from the ureido end, whereas the hole generated at the carboxylate end does not migrate. However, hole migration has been reported to occur from both ends (amino and carboxylate ends) in glycine oligopeptides, and our studies show that the ability to transfer and migrate charge can be tuned by modifying the donor and acceptor functional groups in both the neutral and cationic charge states. We have analyzed the possibility of hole migration following ionization using DFT-based wave-packet propagation and found its occurrence on a ∼2−5 fs time scale, which reflects the charge-transduction ability of peptidomimetics.

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Section: ■ Introductionmentioning

confidence: 99%

Computational Studies on Structural, Excitation, and Charge-Transfer Properties of Ureidopeptidomimetics

2016

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“…202 A prodrug is a conjugate of a promoiety to a functional group of the drug via a cleavable bond (e.g., ester, amide). The formation of a prodrug transiently changes the physicochemical properties of the drug for improving solubility and/or cell membrane permeation through the intestinal mucosa and/or BBB.…”

Section: Prodrug Strategies For Therapeutic Peptidesmentioning

confidence: 99%

“…To solve this problem, the Borchardt group investigated the formation of cyclic peptide prodrugs that would temporarily stabilize the peptide conformation and, at the same time, change the physicochemical properties of the peptide to favor cell membrane permeation. 202 The idea was that the cyclic peptide prodrugs could be converted to parent peptides after the transport process. Ron and his collaborators developed and studied the cyclic prodrugs of opioid peptides using different promoieties, including "trimethyl lock" phenyl propionic acid, coumarinic acid, acyloxyalkoxy, and oxymethyl-modified coumarinic acid (OMCA) promoieties.…”

Section: Prodrug Strategies For Therapeutic Peptidesmentioning

confidence: 99%

“…Ron and his collaborators developed and studied the cyclic prodrugs of opioid peptides using different promoieties, including "trimethyl lock" phenyl propionic acid, coumarinic acid, acyloxyalkoxy, and oxymethyl-modified coumarinic acid (OMCA) promoieties. 202,206,207 The cyclic peptide prodrugs were constructed by linking the peptide N-terminus to the promoiety via an amide bond and the C-terminus to the promoiety via an ester bond. The subsequent improvement in membrane permeability is due to the stabilized conformation of cyclic peptide prodrug that reduces hydrogen bonding potential, increases hydrophobicity, reduces charges, and increases metabolic stability against exo-and endopeptidases.…”

Section: Prodrug Strategies For Therapeutic Peptidesmentioning

confidence: 99%

“…202 Reflected in these advances was also Ron's ability to build teams of collaborators from related disciplines. Especially worth mentioning was his long-standing and productive collaborations with Ron's KU faculty colleagues Professor Teruna Siahaan and David Vander Velde (now at CalTech).…”

Section: Prodrug Strategies For Therapeutic Peptidesmentioning

confidence: 99%

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Recognized as the most common of the neurodegenerative disorders, Alzheimer's disease (AD) affects greater than 18 million people worldwide and is predicted to become the largest socioeconomic burden of the twenty‐first century. The underlying mechanism of Alzheimer's disease is as yet unknown, but the growing body of pathophysiologic evidence is beginning to point to two main causes, the formation of β‐amyloid plaques and neurofibrillary tangles. This review will cover approaches to disease modification that are based on the amyloid hypothesis; that being, the prevention of the accumulation, aggregation, and deposition of β‐amyloid peptide (Aβ) monomers, leading first to multiple oligomeric species and then to fibrils and ultimately senile plaques, is the center of focus for an approach to disease modification. There is a wealth of evidence to implicate this peptide and its subsequent aggregation in the etiology of the disease and approaches, both small molecule and biopharmaceutical, to prevent its accumulation have been the subject of much research. The vast majority of this research over the last decade has been, and continues to be, focused on these disease‐modifying, antiamyloidogenic approaches to AD. It is this subject, and the various approaches, past and present to amelioration of AD through the various agents being explored, that will be the focus of this chapter.

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Improvement of oral peptide bioavailability: Peptidomimetics and prodrug strategies

Cited by 196 publications

References 160 publications

Computational Studies on Structural, Excitation, and Charge-Transfer Properties of Ureidopeptidomimetics

Computational Studies on Structural, Excitation, and Charge-Transfer Properties of Ureidopeptidomimetics

A Tribute to Ronald T. Borchardt—Teacher, Mentor, Scientist, Colleague, Leader, Friend, and Family Man

Approaches to Amyloid Therapies for the Treatment of Alzheimer's Disease

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