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. Herein, we performed -based SAR studies focused on all aliphatic residues and Ala, discovering that the incorporations of Trp and Ile at positions 32 and 38, respectively, enhanced the inhibitory activity. Combining these findings with , a novel peptide displayed an IC value of 0.32 μM, which is 11 times more potent than . The peptide would have the potential to be a promising drug lead to develop better peptidomimetics.
A new benzophenone-diketopiperazine-type potent antimicrotubule agent was developed by modifying the structure of the clinical candidate plinabulin (1). Although the right-hand imidazole ring with a branched alkyl chain at the 5-position in 1 was critical for the potency of the antimicrotubule activity, we successfully substituted this moiety with a simpler 2-pyridyl structure by converting the left-hand ring from a phenyl to a benzophenone structure without decreasing the potency. The resultant compound 6b (KPU-300) exhibited a potent cytotoxicity, with an IC50 value of 7.0 nM against HT-29 cells, by strongly binding to tubulin (K d = 1.3 μM) and inducing microtubule depolymerization.
Although several approaches for making antibody-drug conjugates (ADC) have been developed, it has yet to be reported that an antibody binding peptide such as Z33 from protein A is utilized as the pivotal unit to generate the noncovalent-type ADC (NC-ADC). Herein we aim to establish a novel probe for NC-ADC by synthesizing the Z33-conjugated antitumor agent, plinabulin. Due to the different solubility of two components, including hydrophobic plinabulin and hydrophilic Z33, an innovative method with a solid-supported disulfide coupling reagent is required for the synthesis of the target compounds with prominent efficiency (29% isolated yield). We demonstrate that the synthesized hybrid exhibits a binding affinity against the anti-HER2 antibody (Herceptin) and the anti-CD71 antibody (6E1) (Kd = 46.6 ± 0.5 nM and 4.5 ± 0.56 μM, respectively) in the surface plasmon resonance (SPR) assay. In the cell-based assays, the hybrid provides a significant cytotoxicity in the presence of Herceptin against HER2 overexpressing SKBR-3 cells, but not against HER2 low-expressing MCF-7 cells. Further, it is noteworthy that the hybrid in combination with Herceptin induces cytotoxicity against Herceptin-resistant SKBR-3 (SKBR-3HR) cells. Similar results are obtained with the 6E1 antibody, suggesting that the synthesized hybrid can be widely applicable for NC-ADC using the antibody of interest. In summary, a series of evidence presented here strongly indicate that NC-ADCs have high potential for the next generation of antitumor agents.
In this paper, a new disulfide-forming agent based on the finding that alkoxy 3-nitro-2-pyridinesulfenates (Npys-OR) can oxidize thiol groups is reported. Methyl 3-nitro-2-pyridinesulfenate (Npys-OMe), which is easily prepared from 3-nitro-2-pyridinesulfenyl chloride in a one-step reaction and has a reduction peak potential (E ) of -0.541 V versus Ag/AgCl, produces the cyclic nonapeptide oxytocin from its linear form in good yield (92 %) with minimal oligomer formation. Npys-OMe in the solid phase also demonstrated excellent results in oxytocin synthesis. Other disulfide-containing peptides, such as α-human atrial natriuretic peptide and α-conotoxin ImI, were also successfully synthesized. During these syntheses, no side reactions of methionine (Met) and tryptophan (Trp) residues or the S-acetamidomethyl (Acm) protecting group were detected. These results suggested that Npys-OMe or its solid-phase analog provides a new strategy for regioselective disulfide bond formation to assist the synthesis of complex disulfide-rich peptides.
A revised structure of natural 14-mer cyclic depsipeptide MA026, isolated from Pseudomonas sp. RtlB026 in 2002 was established by physicochemical analysis with HPLC, MS/MS, and NMR and confirmed by total solid-phase synthesis. The revised structure differs from that previously reported in that two amino acid residues, assigned in error, have been replaced. Synthesized MA026 with the revised structure showed a tight junction (TJ) opening activity like that of the natural one in a cell-based TJ opening assay. Bioinformatic analysis of the putative MA026 biosynthetic gene cluster (BGC) of RtIB026 demonstrated that the stereochemistry of each amino acid residue in the revised structure can be reasonably explained. Phylogenetic analysis with xantholysin BGC indicates an exceptionally high homology (ca. 90 %) between xantholysin and MA026. The TJ opening activity of MA026 when binding to claudin-1 is a key to new avenues for transdermal administration of large hydrophilic biologics.
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