330807-46-0Relevant academic research and scientific papers
Ribosomal Synthesis of Macrocyclic Peptides in Vitro and in Vivo Mediated by Genetically Encoded Aminothiol Unnatural Amino Acids
Frost, John R.,Jacob, Nicholas T.,Papa, Louis J.,Owens, Andrew E.,Fasan, Rudi
, p. 1805 - 1816 (2015/09/01)
A versatile method for orchestrating the formation of side chain-to-tail cyclic peptides from ribosomally derived polypeptide precursors is reported. Upon ribosomal incorporation into intein-containing precursor proteins, designer unnatural amino acids be
Synthesis of unsymmetrical troeger's bases bearing groups sensitive to reduction
Havlik, Martin,Dolensky, Bohumil,Jakubek, Milan,Kral, Vladimir
, p. 2798 - 2805 (2014/05/06)
An efficient approach for the synthesis of unsymmetrically substituted Troeger's base derivatives is reported. This approach is based on the N-alkylation of an arylamine by tert-butyl [2-(bromomethyl)aryl]carbamate to give the corresponding diamine, which
Macrocyclization of Organo-Peptide Hybrids through a Dual Bio-orthogonal Ligation: Insights from Structure-Reactivity Studies
Frost, John R.,Vitali, Francesca,Jacob, Nicholas T.,Brown, Micah D.,Fasan, Rudi
, p. 147 - 160 (2013/02/26)
Macrocycles constitute an attractive structural class of molecules for targeting biomolecular interfaces with high affinity and specificity. Here, we report systematic studies aimed at exploring the scope and mechanism of a novel chemo-biosynthetic strategy for generating macrocyclic organo-peptide hybrids (MOrPHs) through a dual oxime-/intein-mediated ligation reaction between a recombinant precursor protein and bifunctional, oxyamino/1,3-amino-thiol compounds. An efficient synthetic route was developed to access structurally different synthetic precursors incorporating a 2-amino- mercaptomethyl-aryl (AMA) moiety previously found to be important for macrocyclization. With these compounds, the impact of the synthetic precursor scaffold and of designed mutations within the genetically encoded precursor peptide sequence on macrocyclization efficiency was investigated. Importantly, the desired MOrPHs were obtained as the only product from all the different synthetic precursors probed in this study and across peptide sequences comprising four to 15 amino acids. Systematic mutagenesis of the "i-1" site at the junction between the target peptide sequence and the intein moiety revealed that the majority of the 20 amino acids are compatible with MOrPH formation; this enables the identification of the most and the least favorable residues for this critical position. Furthermore, interesting trends with respect to the positional effect of conformationally constrained (Pro) and flexible (Gly) residues on the reactivity of randomized hexamer peptide sequences were observed. Finally, mechanistic investigations enabled the relative contributions of the two distinct pathways (side-chain→C-end ligation versus C-end→side-chain ligation) to the macrocyclization process to be dissected. Altogether, these studies demonstrate the versatility and robustness of the methodology to enable the synthesis and diversification of a new class of organo-peptide macrocycles and provide valuable structure-reactivity insights to inform the construction of macrocycle libraries through this chemo-biosynthetic strategy.
Fine tuning of the cation affinity of artificial receptors based on cyclic peptides by intramolecular conformational control
Kubik, Stefan,Goddard, Richard
, p. 311 - 322 (2007/10/03)
A series of cyclic hexapeptides consisting of alternating 4-substituted 3-aminobenzoic acid units (R = CH3, Cl, CH2OCH3, OCH3, COOCH3) and residues of the natural amino acid proline has been prepared and their ion affinities have been investigated. Whereas the unsubstituted parent compound (R = H) is able to bind cations through cation-π interactions with the aromatic subunits, as well as anions through hydrogen bonding with the peptide NH groups, the introduction of substituents at the 4-positions of the aromatic rings results in complete loss of the anion affinity. The cation complex stabilities depend on the substituents and cover a wide range from Ka = 140 M-1 for R = CH3 to Ka = 10800 M-1 for R = COOCH3 (Ka = 1260 M-1 for R = H) with n-butyltrimethylammonium picrate. The conformations of the peptides in solution have been determined by one-and two-dimensional NMR techniques and FT-IR spectroscopy. It was found that all the substituents prevent the peptides from adopting the necessary conformation for anion binding. For one receptor (R = OCH3), the results have been corroborated by a crystal structure determination. AM1 calculations have been used to estimate the electrostatic potential surfaces of the substituted aromatic subunits. The variation in the cation complex stabilities can be mainly attributed to the effects of the substituents on the solution conformations of the peptides. The influence of the substituents on the electrostatic potentials of the aromatic peptide subunits appears to be less important.
