X-Ray Conformation and Structure-Activity Relationships of MA026, a Reversible Tight Junction Opener.

MA026, a cyclic lipodepsipeptide, opens the tight junction (TJ) probably via binding to claudin-1. We reported that (1) TJ-opening activity is dependent on the amino acid sequence order at Glu10-Leu11; (2) an epimer at the C3 position of the -terminal acyl tail decreased the TJ-opening activity; and (3) the epimers D-Leu1/L-Gln6 and L-Leu1/D-Gln6 showed more potent TJ-opening activity than natural MA026, although no systematic structure-activity relationship (SAR) study was conducted. Here, we report the three-dimensional structure and systematic SAR study of MA026.

Design and synthesis of peptidic partial agonists of human neuromedin U receptor 1 with enhanced serum stability.

Neuromedin U (NMU) activates two receptors (NMUR1 and NMUR2) and is a promising candidate for development of drugs to combat obesity. Previously, we obtained hexapeptides as selective full NMUR agonists. Development of a partial agonist which mildly activates receptors is an effective strategy which lead to an understanding of the functions of NMU receptors.

Chain-Shortened Myostatin Inhibitory Peptides Improve Grip Strength in Mice.

Inhibition of myostatin is a promising strategy for treatment of muscle atrophic disorders. We had already identified a 23-mer peptide () as a synthetic myostatin inhibitor, and structure-activity relationship studies with afforded a potent 22-mer peptide derivative (). Herein, we report the shortest myostatin inhibitory peptide so far.

Development of Potent Myostatin Inhibitory Peptides through Hydrophobic Residue-Directed Structural Modification.

Myostatin, a negative regulator of skeletal muscle growth, is a promising target for treating muscle atrophic disorders. Recently, we discovered a minimal myostatin inhibitor (WRQNTRYSRIEAIKIQILSKLRL-amide) derived from positions 21-43 of the mouse myostatin prodomain. We previously identified key residues (N-terminal Trp, rodent-specific Tyr, and all aliphatic amino acids) required for effective inhibition through structure-activity relationship (SAR) studies based on and characterized a 3-fold more potent inhibitor bearing a 2-naphthyloxyacetyl group at position 21.

Structural Basis for the Effective Myostatin Inhibition of the Mouse Myostatin Prodomain-Derived Minimum Peptide.

Myostatin inhibition is one of the promising strategies for treating muscle atrophic disorders, including muscular dystrophy. It is well-known that the myostatin prodomain derived from the myostatin precursor acts as an inhibitor of mature myostatin. In our previous study, myostatin inhibitory minimum peptide (WRQNTRYSRIEAIKIQILSKLRL-amide) was discovered from the mouse myostatin prodomain.

Effect of N-Terminal Acylation on the Activity of Myostatin Inhibitory Peptides.

Inhibition of myostatin, which negatively regulates skeletal muscle growth, is a promising strategy for the treatment of muscle atrophic disorders, such as muscular dystrophy, cachexia and sarcopenia. Recently, we identified peptide A (H-WRQNTRYSRIEAIKIQILSKLRL-NH2 ), the 23-amino-acid minimum myostatin inhibitory peptide derived from mouse myostatin prodomain, and highlighted the importance of its N-terminal tryptophan residue for the effective inhibition. In this study, we synthesized a series of acylated peptide derivatives focused on the tryptophan residue to develop potent myostatin inhibitors.

Identification of the minimum peptide from mouse myostatin prodomain for human myostatin inhibition.

Myostatin, an endogenous negative regulator of skeletal muscle mass, is a therapeutic target for muscle atrophic disorders. Here, we identified minimum peptides 2 and 7 to effectively inhibit myostatin activity, which consist of 24 and 23 amino acids, respectively, derived from mouse myostatin prodomain. These peptides, which had the propensity to form α-helix structure, interacted to myostatin with KD values of 30-36 nM.