Backbone cyclization: A new method for conferring conformational constraint on peptides

Gilon, Chaim; Halle, David; Chorev, Michael; Selinger, Zvi; Byk, Gérardo

doi:10.1002/bip.360310619

Cited by 204 publications

(186 citation statements)

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“…Intramolecular cyclization has been demonstrated to improve biological properties of bioactive peptides [28][29][30][31][32][33][34][35][36][37][38], in many cases allowing one to improve selectivity for a given receptor and/or metabolic stability [39][40][41]. Cyclic peptides can be divided into homodetic and heterodetic, the first being obtained by formation of an intramolecular peptide (amide) bond, whereas heterodetic refers to all cyclic peptides where the intramolecular bond newly formed is other than an amide (e.g., lactone, ether, thioether and, most commonly, disulphide bridges).…”

Section: Peptide Carriers A) Peptide Cyclization and Prodrug Designmentioning

confidence: 99%

“…Cyclic peptides can be divided into homodetic and heterodetic, the first being obtained by formation of an intramolecular peptide (amide) bond, whereas heterodetic refers to all cyclic peptides where the intramolecular bond newly formed is other than an amide (e.g., lactone, ether, thioether and, most commonly, disulphide bridges). Scheme 10 summarizes intramolecular cyclizations that peptides can undergo, which can be split into three categories: a) classical routes (head-to-tail, head-to-side chain, side chain-to-side chain and side chain-to-tail cyclizations); b) N-backbone cyclization; and, c) C-backbone cyclization [39,42]. The concept of backbone cyclization was introduced by Gilon et al in 1991 to stabilize the peptide bioactive conformation without affecting its functional groups [39].…”

Section: Peptide Carriers A) Peptide Cyclization and Prodrug Designmentioning

confidence: 99%

“…Scheme 10 summarizes intramolecular cyclizations that peptides can undergo, which can be split into three categories: a) classical routes (head-to-tail, head-to-side chain, side chain-to-side chain and side chain-to-tail cyclizations); b) N-backbone cyclization; and, c) C-backbone cyclization [39,42]. The concept of backbone cyclization was introduced by Gilon et al in 1991 to stabilize the peptide bioactive conformation without affecting its functional groups [39]. From Scheme 10, one can easily infer that peptide cyclization could be used in prodrug design by two different approaches: (i) linear peptides acting as cyclization-activated prodrugs of bioactive cyclic peptides; (ii) linear peptides acting as drug carriers in prodrugs that can be activated through cyclization of the peptide moiety.…”

Section: Peptide Carriers A) Peptide Cyclization and Prodrug Designmentioning

confidence: 99%

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Cyclization-activated Prodrugs

2007

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Many drugs suffer from an extensive first-pass metabolism leading to drug inactivation and/or production of toxic metabolites, which makes them attractive targets for prodrug design. The classical prodrug approach, which involves enzyme-sensitive covalent linkage between the parent drug and a carrier moiety, is a well established strategy to overcome bioavailability/toxicity issues. However, the development of prodrugs that can regenerate the parent drug through non-enzymatic pathways has emerged as an alternative approach in which prodrug activation is not influenced by inter-and intraindividual variability that affects enzymatic activity. Cyclization-activated prodrugs have been capturing the attention of medicinal chemists since the middle-1980s, and reached maturity in prodrug design in the late 1990s. Many different strategies have been exploited in recent years concerning the development of intramoleculary-activated prodrugs spanning from analgesics to anti-HIV therapeutic agents. Intramolecular pathways have also a key role in two-step prodrug activation, where an initial enzymatic cleavage step is followed by a cyclization-elimination reaction that releases the active drug. This work is a brief overview of research on cyclization-activated prodrugs from the last two decades.

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Section: Peptide Carriers A) Peptide Cyclization and Prodrug Designmentioning

confidence: 99%

Section: Peptide Carriers A) Peptide Cyclization and Prodrug Designmentioning

confidence: 99%

Section: Peptide Carriers A) Peptide Cyclization and Prodrug Designmentioning

confidence: 99%

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Cyclization-activated Prodrugs

2007

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“…Backbone cyclization of peptides is the method of cyclization developed and used in our lab. It results in peptides with improved selectivity, enhanced metabolic stability, and high bioavailability (5)(6)(7)(8)(9). To select the most active backbone cyclic (BC) 1 peptide based on a given sequence, we have developed the "cycloscan" technology (10), which involves the structure-based design, synthesis, and screening of BC peptide libraries.…”

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confidence: 99%

Development of a Functional Backbone Cyclic Mimetic of the HIV-1 Tat Arginine-rich Motif

Friedler¹,

Friedler²,

Luedtke³

et al. 2000

Journal of Biological Chemistry

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We have used the backbone cyclic proteinomimetics approach to develop peptides that functionally mimic the arginine-rich motif (ARM) of the HIV-1 Tat protein. This consensus sequence serves both as a nuclear localization signal (NLS) and as an RNA binding domain. Based on the NMR structure of Tat, we have designed and synthesized a backbone cyclic ARM mimetic peptide library. The peptides were screened for their ability to mediate nuclear import of the corresponding BSA conjugates in permeabilized cells. One peptide, designated "Tat11," displayed active NLS properties. Nuclear import of Tat11-BSA was found to proceed by the same distinct pathway used by the Tat-NLS and not by the common importin ␣ pathway, which is used by the SV40-NLS. Most of the Tat-derived backbone cyclic peptides display selective inhibitory activity as demonstrated by the inhibition of the nuclear import mediated by the Tat-NLS and not by the SV40-NLS. The Tat-ARM-derived peptides, including Tat-11, also inhibited binding of the HIV-1 Rev-ARM to its corresponding RNA element (Rev response element) with inhibition constants of 5 nM. Here we have shown for the first time (a) a functional mimetic of a protein sequence, which activates a nuclear import receptor and (b) a mimetic of a protein sequence with a dual functionality. Tat11 is a lead compound which can potentially inhibit the HIV-1 life cycle by a dual mechanism: inhibition of nuclear import and of RNA binding.Proteinomimetics are small molecules that can mimic the structure and/or function of active sites within proteins (1). They are useful for detailed study of protein folding, structure, and function. The major potential application of proteinomimetics is, however, therapeutic; such molecules can be used to block protein-protein and/or protein-nucleic acid interactions, thus interfering with undesired biological processes (2-4). Being relatively small, proteinomimetics often solve acute problems associated with the use of proteins as drugs, such as antigenicity, low bioavailability, high cost, and rapid enzymatic degradation.Two properties of the parent protein must be retained when designing proteinomimetics: (i) the bioactive conformation of the desired active site and (ii) a certain degree of conformational flexibility to allow induced fit. Linear peptides are not optimal candidates to mimic proteins, because they equilibrate between multiple conformations and thus adaptation of the bioactive conformation is at an entropic cost. Introduction of conformational constraints into the peptide is thus needed to generate a proteinomimetic. Being relatively small and conformationally constrained, cyclic peptides are excellent candidates to serve as proteinomimetics. Backbone cyclization of peptides is the method of cyclization developed and used in our lab. It results in peptides with improved selectivity, enhanced metabolic stability, and high bioavailability (5-9). To select the most active backbone cyclic (BC) 1 peptide based on a given sequence, we have developed the "cycloscan" ...

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“…When additional degrees of freedom are considered (e.g., bond angle bending or bond length stretching), the accessible conformational space is even larger (8,9). As a consequence, unless there are unusual amino acids in a peptide sequence (10,11) and/or the peptide is cyclic (12), most small peptides will have multiple conformations in solution. In proteins, long-range interactions lead to cooperative folding (13) and low-energy conformations which include structures such as f3-sheets and helices (a or 310).…”

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confidence: 99%

Designing amino acids to determine the local conformations of peptides.

Burgess

1994

Proc. Natl. Acad. Sci. U.S.A.

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The local conformations of proteins and peptides are determined by the amino acid sequence. However, the 20 amino acids encoded by the genome allow the peptide backbone to fold Into many conformations, so that even for a smail peptide It becomes very difficult to predict the threedimensional structure. By using empirical conformational energy calculations a set of amino acids has been designed that would be expected to constrain the conformation of a peptide or a protein to one or two local minima. Most of these amino acids are based on asymmetric ubstItutions at the Ca atom of each residue. The HO atom of alanine was repad by various groups: -OCH3, -NCH3, -SCH3, -CONH2, -CONHCH3, -CON(CH3)2, -NH CO CH3, -phenyl, or -o-(OCH3)phenyl. Several of these new amino acids are pedt to fold into unique peptide conformations such as right-handed a-helical, left-handed a-helical, or extended. In an attempt to produce an amino acid that fvored the CV' conformation (torsion angles: * = -70 and # = +70%), an extra amide group was added to the CP atom of the asparagine side chain. Conformationally restried amino acids of this type could prove useful for developing new peptide pharmaceuticals, catalysts, or polymers.The prediction of the three-dimensional structures of peptides and proteins is not yet possible (1, 2). In part, the difficulties stem from the intrinsic conformational freedom associated with each amino acid in the polypeptide chain (3, 4). If we assume that the conformational freedom is determined essentially by the 4 and 4 rotations about the N-Ca and Cat-C' bonds, respectively, almost all ofthe amino acids except proline and glycine are able to access -30% of the two-dimensional (4, *) conformational space (5). Proline restricts the conformational freedom considerably (6), whereas glycine allows access to >60%6 of the total (4, @) rotational space (7). When additional degrees of freedom are considered (e.g., bond angle bending or bond length stretching), the accessible conformational space is even larger (8, 9). As a consequence, unless there are unusual amino acids in a peptide sequence (10,11) and/or the peptide is cyclic (12), most small peptides will have multiple conformations in solution. In proteins, long-range interactions lead to cooperative folding (13) and low-energy conformations which include structures such as f3-sheets and helices (a or 310).However, constraints on the local conformation of the polypeptide chain are relatively weak, thus predicting a priori that the preferred local conformation of a peptide requires an accurate comparison of the enormous numbers of possible conformations. Even the relatively simple task of redesigning peptide loops by homology modeling requires approximations that hinder the reliability of these calculations (2,14,15), and when there is no highly homologous structure, the semi-empirical calculations are not yet sufficiently powerful to generate a reliable model of the three-dimensional structure.Small peptides are ubiquitous regulators in many biological s...

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Backbone cyclization: A new method for conferring conformational constraint on peptides

Cited by 204 publications

References 19 publications

Cyclization-activated Prodrugs

Cyclization-activated Prodrugs

Development of a Functional Backbone Cyclic Mimetic of the HIV-1 Tat Arginine-rich Motif

Designing amino acids to determine the local conformations of peptides.

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