Prodrugs of Peptides and Proteins for Improved Formulation and Delivery

Oliyai, Reza; Stella, Valentino J.

doi:10.1146/annurev.pa.33.040193.002513

Cited by 81 publications

(34 citation statements)

References 102 publications

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“…Amino acid-based drugs generally have a low bioavailability due to low intestinal permeability, extensive metabolism in the intestines, and a rapid clearance by the liver [1]. Thus, the prodrug strategy, a transient modification of physicochemical properties through chemical derivatization, is the approach of choice for such drugs [1,2].…”

Section: Introductionmentioning

confidence: 99%

“…Thus, the prodrug strategy, a transient modification of physicochemical properties through chemical derivatization, is the approach of choice for such drugs [1,2]. L-Tyrosine carboxylic esters can be used as prodrugs [3][4][5] for example as antinociceptive [3], while some L-tyrosine derivatives have been proposed for the treatment of Parkinson disease [6,7].…”

Section: Introductionmentioning

confidence: 99%

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Tyrosine alkyl esters as prodrug: the structure and intermolecular interactions of l-tyrosine methyl ester compared to l-tyrosine and its ethyl and n-butyl esters

et al. 2011

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L-Tyrosine alkyl esters are used as prodrugs for L-tyrosine. Although prodrugs are often designed for their behavior in solution, understanding their solid-state properties is the first step in mastering drug delivery. The crystal structure of L-tyrosine methyl ester has been determined and compared to published structures of L-tyrosine and its ethyl and n-butyl esters. It is almost isostructural with the other esters: it crystallizes in the orthorhombic chiral space group P2 1 2 1 2 1 , a = 5.7634(15) Å , b = 12.111(2) Å , c = 14.3713(19) Å , V = 1003.1(4) Å 3 with Z 0 = 1. Their main packing motif is a C(9) infinite hydrogen-bond chain, but the conformation of L-tyrosine methyl ester is different from the other two: eclipsed versus U-shaped, respectively. The published structure of the ethyl ester, which was incomplete, has been confirmed by X-ray powder diffraction data. Because L-tyrosine methyl ester is very stable (28 years stored at room temperature), and its hydrolysis rate is relatively low, it should be one of the better prodrugs among the alkyl esters of tyrosine.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Tyrosine alkyl esters as prodrug: the structure and intermolecular interactions of l-tyrosine methyl ester compared to l-tyrosine and its ethyl and n-butyl esters

et al. 2011

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“…Based on previous work on the synthesis of the more soluble o-acyl prodrug analogs [149,150], this technique involves the assembly of the O-acyl isopeptide and its later conversion to its peptide counterpart under physiological conditions (Scheme 2.4). Due to the better solubility of the O-acyl isoform, this is obtained in better yields and purities.…”

Section: O-acyl Isopeptidementioning

confidence: 99%

Methods for the Peptide Synthesis and Analysis

Tulla‐Puche

El‐Faham

Galanis

et al. 2015

Peptide Chemistry and Drug Design

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“…The number of identified endogenous peptides is growing exponentially; recently, almost 600 sequences for neuropeptides and related peptides have been listed [606]. However, delivery of peptides through the BBB is an even more complex problem than delivery of other drugs because they can be rapidly inactivated by ubiquitous peptidases [420,[607][608][609][610]. For peptides, it is usually quite difficult to build up and to maintain effective blood levels in general, because they are very efficiently metabolized and eliminated-not a surprising observation if one considers that their name comes from the Greek peptoz (peptos) meaning "digestible."…”

Section: Molecular Packagingmentioning

confidence: 99%

Retrometabolism‐Based Drug Design and Targeting

Bodor

Buchwald

2010

Burger's Medicinal Chemistry and Drug Discovery

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Retrometabolic drug design (RMDD) approaches are systematic methodologies aimed to design safe compounds with an improved therapeutic index. RMDDs thoroughly integrate structure– activity and structure‐metabolism considerations into the entire design process and incorporate two major concepts aimed to design soft drugs and chemical delivery systems, respectively. Soft drugs (SDs) are new, active therapeutic agents designed to undergo predictable metabolism resulting in inactive metabolites after exerting their desired therapeutic effect(s). Chemical delivery systems (CDSs) are biologically inert molecules that provide enhanced and targeted delivery of an active drug to a particular organ or site through a designed sequential metabolism that involves several steps. Here, we present a comprehensive review including a general overview of the RMDD principles and a large number of specific examples from various pharmacological areas, including many recent developments, to illustrate RMDD concepts. Whenever possible, the rationale for the design as well as the pharmacokinetic and pharmacodynamic properties of the new therapeutic agents are briefly summarized and compared to those of the other compounds used in the same field.

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Prodrugs of Peptides and Proteins for Improved Formulation and Delivery

Cited by 81 publications

References 102 publications

Tyrosine alkyl esters as prodrug: the structure and intermolecular interactions of l-tyrosine methyl ester compared to l-tyrosine and its ethyl and n-butyl esters

Tyrosine alkyl esters as prodrug: the structure and intermolecular interactions of l-tyrosine methyl ester compared to l-tyrosine and its ethyl and n-butyl esters

Methods for the Peptide Synthesis and Analysis

Retrometabolism‐Based Drug Design and Targeting

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