Selectivity enhancement induced by substitution of non-natural analogues of arginine and lysine in arginine-based thrombin inhibitors

Trypsin inhibition by macrocyclic and open-chain variants of the squash inhibitor MCoTI-II

“…It was concluded that trypsin inhibition depends not only on the basicity of the P1 residue, but also on steric factors, since a peptide containing ornithine, an amino acid that differs from lysine only by a single methylene group, had no measurable trypsin inhibitory activity (Domingo et al, 1995). In light of these previous findings, it is interesting to note that oMCoTIAlaG retains measurable residual trypsin inhibitory activity, albeit approximately four orders of magnitude lower compared to oMCoTI-II and oMCoTI-II R10 , corroborating the ability of non-natural arginine analogues to act as basic P1 residues in serine protease inhibitors (Kokko et al, 2001;McBride and Leatherbarrow, 2001). To understand the influence of steric effects of the AlaG side chain on trypsin binding and inhibition, structural information is required.…”

Identification and Functional Characterization of a Stable, Centrally Active Derivative of the Neurotensin (8−13) Fragment as a Potential First-in-Class Analgesic

“…It also has been shown to have potential as an antipsychotic compound based on its blockade of amphetamine-induced locomotor hyperactivity 7–8. NT exerts its effects through binding of two brain receptors, NTR-1 (also referred to as NTS-1) and NTR-2 (NTS-2), although the relative roles of each receptor in the physiological responses are not well-understood 9–11. Numerous experiments with both NT and NT(8–13) suggest that all central activities attributable to NT and derivatives only manifest following direct application into the CNS 12 while peripheral administration is ineffectual.…”

Design, Synthesis, Molecular Dynamics Simulation, and Functional Evaluation of a Novel Series of 26RFa Peptide Analogues Containing a Mono- or Polyalkyl Guanidino Arginine Derivative

“…41,42 The selectivity of peptide-based thrombin inhibitors is also modulated by this kind of modification. 43 Similarly, specific peptide inhibitors targeting the substrate arginine-binding site of protein arginine N-methyltransferases and containing a single N ω -ethyl-arginine residue have been designed. 44,45 Incorporation of N ω -alkyl-arginine into peptides was also shown to increase lipophilicity 37,46 and to modify the basicity of the N-alkyl-guanidino group.…”

“…Replacement of arginine residues by guanidino-alkylated derivatives within bioactive peptide sequences was previously found to improve stability of Kiss1R agonists toward digestion by trypsin-like proteases to emulate bradykinin B2 receptor affinity of the Hoe 140 antagonist and to enhance potency and duration of activity of GnRH antagonists. , The selectivity of peptide-based thrombin inhibitors is also modulated by this kind of modification . Similarly, specific peptide inhibitors targeting the substrate arginine-binding site of protein arginine N -methyltransferases and containing a single N ω -ethyl-arginine residue have been designed. , Incorporation of N ω -alkyl-arginine into peptides was also shown to increase lipophilicity , and to modify the basicity of the N -alkyl-guanidino group. , Generally, the alkyl substituent reduces available hydrogen bonding to the guanidino group while retaining a positive charge at physiological pH and consequently modifies the peptide–receptor interactions of the alkylated ligand.…”