Chaim Gilon | The Hebrew University of Jerusalem (original) (raw)

Papers by Chaim Gilon

Angewandte Chemie (International ed. in English), Jan 18, 2017

A highly systematic approach for the development of both orally bioavailable and bioactive cyclic... more A highly systematic approach for the development of both orally bioavailable and bioactive cyclic N-methylated hexapeptides as high affinity ligands for the integrin αvβ3 is based on two concepts: a) screening of systematically designed libraries with spatial diversity and b) masking of the peptide charge with a lipophilic protecting group. The key steps of the method are 1) initial design of a combinatorial library of N-methylated analogues of the stem peptide cyclo(d-Ala-Ala5 ); 2) selection of cyclic peptides with the highest intestinal permeability; 3) design of sublibraries with the bioactive RGD sequence in all possible positions; 4) selection of the best ligands for RGD-recognizing integrin subtypes; 5) fine-tuning of the affinity and selectivity by additional Ala to Xaa substitutions; 6) protection of the charged functional groups according to the prodrug concept to regain intestinal and oral permeability; 7) proof of biological effects in mice after oral administration.

Beilstein Journal of Organic Chemistry, 2017

Several multistep strategies were developed to ensure single methylation of amines on solid suppo... more Several multistep strategies were developed to ensure single methylation of amines on solid support. These strategies rely on the introduction of the o-NBS protecting/activating group as a key step. We found that the state-of-the-art strategies fail for the methylation of several primary amine motifs, largely due to inefficient sulfonylation. Here we show that using the superior nucleophilic base DMAP instead of the commonly used base collidine as a sulfonylation additive is essential for the introduction of the o-NBS group to these amine motifs. DFT calculations provide an explanation by showing that the energy barrier of the DMAP intermediate is significantly lower than the one of the collidine. We demonstrate that using DMAP as a sole additive in the sulfonylation step results in an overall effective and regioselective N-methylation. The method presented herein proved highly efficient in solid-phase synthesis of a somatostatin analogue bearing three N α-methylation sites that cou...

Journal of Peptide …, 1996

Novel backbone-to-side chain a n d backbone-to-backbone cyclic analogues of substance P (SP) were... more Novel backbone-to-side chain a n d backbone-to-backbone cyclic analogues of substance P (SP) were prepared by solid-phase synthesis a n d screened for biological activity. An analogue containing a thioetherlactam ring between positions 9 and 1 1 showed an ECm value of 20 rn toward the neurokinin 1 (NK-1) and was inactive toward the NK-2 and NK-3 receptors. On the other hand, in a multiple backbone cyclic peptide library of similar analogues, in which the sulphur was excluded from the ring, very low activity was detected. The activity was re-evaluated a n d was found to be even lower (ECS0 = 0.1 1 m) than the previously published data. These results indicate that the thioether moiety has a crucial role in receptor activation. The results also show tolerance of the NK-1 receptor, but not NK-2 or NK-3, to cyclization of the C-terminal portion of the SP,, hexapeptide.

Bioorganic Medicinal Chemistry, Jan 15, 2010

A peptide-peptoid hybrid (peptomer) library was designed and synthesized, based on the sequence P... more A peptide-peptoid hybrid (peptomer) library was designed and synthesized, based on the sequence Phe-D-Phe-Arg-Trp-Gly. This sequence was previously found to specifically activate the melanocortin-4-receptor (MC4R) which participates in regulation of energy homeostasis and appetite. The library of peptomers included a peptoid bond in the Phe and/or D-Phe position and consisted of linear and backbone cyclic analogs, differed in their ring size. While the linear peptides rapidly degraded in serum and in brush border membrane vesicles (BBMV's), the linear peptomers were more stable. Backbone cyclic peptomers were also stable under the same conditions. Backbone cyclization significantly increased the intestinal permeability of two peptomers compared to their linear counterparts, in the Caco-2 model. Pharmacological evaluation revealed that two linear and one backbone cyclic peptomer, were found active towards MC4R at the nanomolar range. Thus, the conformational constrains imposed by these local and global modifications affect both the pharmacokinetic and pharmacodynamic properties of the parent peptide. This study demonstrates the potential of imposing backbone cyclization on bioactive peptomers as a promising approach in developing an orally available peptidomimetic drug leads.

International Journal of Peptide and Protein Research, 2009

The conformations of two backbone-cyclized substance P analogs were derived from homoand heteronu... more The conformations of two backbone-cyclized substance P analogs were derived from homoand heteronuclear NMR measurements and molecular dynamics simulations carried out in DMSO. The analogs contain subtle variations in the ring chemistry and are compared with biologically active analogs previously examined. The correlation between conformation and activity is used to gain insight into the conformational requirements from the pharmacophore. 0 Munksgaard 1996.

J Org Chem, 1997

An improved synthesis of a family of amino acids that contain omega-aminoalkyl groups and of a ne... more An improved synthesis of a family of amino acids that contain omega-aminoalkyl groups and of a new family containing omega-carboxyalkyl groups linked to the alpha-amine is described. The synthesis was performed by alkylation of suitably monoprotected alkylenediamines and protected omega-amino acids with triflates of alpha-hydroxy acid esters. The reaction proceeded with inversion of configuration yielding optically pure products. The N(alpha)-(omega-aminoalkyl)amino acids and N(alpha)-(omega-carboxyalkyl)amino acids were orthogonally protected to allow their incorporation into peptides by solid-phase peptide synthesis (SPPS) methodology.

J Mol Biol, 1999

The retroviral protease (PR) is absolutely essential for completion of human immunodeficiency vir... more The retroviral protease (PR) is absolutely essential for completion of human immunodeficiency virus multiplication cycle, and cannot be replaced by any cellular function. Thus PR, like reverse transcriptase, is an ideal target for the development of anti-AIDS therapy. A large number of human immunodeficiency virus type-1 (HIV-1) PR inhibitors have been developed, and several are currently used as anti-AIDS drugs. These inhibitors are mainly based on the natural PR cleavage sites within the viral Gag and Gag-Pol precursors. The major difficulty encountered while using anti-HIV therapeutic agents in patients has been the rapid emergence of drug-resistant viral strains. Most of the mutations which convert the PR into inhibitor-resistant are located within the substrate binding subsites of the enzyme. Recently, it has been shown that the HIV-1 auxiliary protein Vif, and especially the N-terminal half of Vif (N′-Vif) specifically interacts with the viral PR and inhibits its activity. We now show that efficient inhibition of HIV-1 PR activity can be achieved using Vif-derived peptides. Based on the above model we have performed peptide mapping of N′-Vif in order to find a small peptidic lead compound which inhibits PR activity. The screening revealed that peptides derived from two regions in Vif spanning from residues 30–65 and 78–98 inhibit PR activity in vitro, specifically bind HIV-PR and inhibit HIV-1 production in vivo. Further mapping of these regions revealed the lead compounds Vif81–88 and Vif88–98. These peptides specifically inhibit and bind HIV-1 PR, but do not affect pepsin and rous sarcoma virus protease. In contrast to other known PR inhibitors, these peptides are not substrate-based and their sequences do not resemble the sequences of the natural PR substrates (cleavage sites). Moreover, the Vif-derived peptides themselves are not cleaved by HIV-1 PR. Conversion of the lead peptides into small backbone cyclic peptidomimetics is taking place nowadays in order to turn these lead compounds into metabolically stable selective novel type of HIV-PR non-substrate-based inhibitors.

J Org Chem, 1992

A variety of new amino acids which contain an w-aminoakylene group on the N' -amino nitrogen were... more A variety of new amino acids which contain an w-aminoakylene group on the N' -amino nitrogen were synthesized by alkylation of alkylenediamines with a-halogeno acids. The reaction proceeds with inversion of configuration; thus, optically pure products were obtained when optically active a-halogeno acids were used. The N-(w-aminoalky1ene)amino acids were protected by orthogonal protecting groups to allow their incorporation into dipeptides by the "solutionn techniques and i n b peptides by the solid-phase peptide synthesis (SPPS) methodology. A series of dipeptide analogs of Phe-Gly, Leu-Gly, Trp-Gly, Phe-Leu, and Phe-Ala in which the nitrogen of the peptide bond is alkylated by w-aminoalkylene chains with various lengths were prepared. These new protected N-(o-aminoalky1ene)amino acids and their derived dipeptide units may be used as building blocks for conformationally constrained N-backbone cyclic peptides.

J Pept Res, 2001

General methods for the preparation of protected Nalpha(omega-thioalkyl) amino acids building uni... more General methods for the preparation of protected Nalpha(omega-thioalkyl) amino acids building units for backbone cyclization using reductive alkylation and on-resin preparation are described. The synthesis of non-Gly Fmoc-protected S-functionalized N-alkylated amino acids is based on the reaction of readily prepared protected omega-thio aldehyde with the appropriate amino acid. Preparation of Fmoc-protected S-functionalized N-alkylated Gly building units was carried out using two methods: reaction of glyoxylic acid with Acm-thioalkylamine and an on-resin reaction of bromoacetyl resin with Trt-thioalkylamines. Three model peptides were prepared using these building units. The GlyS2 building unit was incorporated into a backbone cyclic analog of somatostatin that contains a disulfide bridge. Formation of the disulfide bridge was performed by on-resin oxidation using 12 or Tl(CF3COO-)3. Both methods resulted in the desired product in a high degree of purity in the crude. The AspS3 building unit was also successfully incorporated into a model peptide. In addition, the in situ generation of sulfur containing Gly building units was demonstrated on a Substance P backbone cyclic analog containing a thioether bridge.