Catalysis Driven by an Amyloid-Substrate Complex

Amyloid catalysis is an emerging area of research. Here, we report a new catalysis system, i.e., catalysis driven by amyloid-substrate complex (CASL), by exploiting amyloid binding with the ligands. The ammonium ion attached to the amyloid-binding motif was activated by its proximity to the amyloid catalyst, formed by Ac-Asn-Phe-Gly-Ala-Ile-Leu-NH2 (NL6) derived from islet amyloid polypeptide (IAPP), thereby promoting amine modifications in the acidic buffer. Consistent with the mode of action of CASL, the affinity of the substrates with amyloid catalysts correlated with the reaction yields. In addition, the direction of the amine extension from the amyloid-binding site markedly influenced the reaction progress. Crystallographic analysis and amide-to-ester substitution of the amyloid catalysts indicated that the carbonyl oxygen of the Phe–Gly amide bond of NL6 played a key role in activating the substrate amine via forming a hydrogen bond. With CASL, we succeeded in the selective conversion of substrates possessing equivalently reactive amine functionalities and introduced a new reaction scope (various amine modifications) to catalytic reactions using amyloids. The substrate-selective conversion ability of CASL significantly expands the applicability of catalytic amyloids in diverse research fields, including chemical biology and materials science

Promotion in the Clearance of Aggregated Aβ In Vivo Using Amyloid Selective Photo-Oxygenation Technology

Alzheimer’s disease (AD) is characterized by the aggregation and deposition of 2 amyloid proteins: amyloid β peptide (Aβ) and tau protein. Immunotherapies using anti-Aβ antibodies to promote the clearance of aggregated Aβ have recently been highlighted as a promising disease-modifying approach against AD. However, immunotherapy has still some problems, such as low efficiency of delivery into the brain and high costs. We have developed the “amyloid selective photo-oxygenation technology” as a comparable to immunotherapy for amyloids. The photo-oxygenation can artificially attach the oxygen atoms to specific amino acids in amyloid proteins using photocatalyst and light irradiation. We revealed that in vivo photo-oxygenation for living AD model mice reduced the aggregated Aβ in the brain. Moreover, we also showed that microglia were responsible for this promoted clearance of photo-oxygenated Aβ from the brain. These results indicated that our photo-oxygenation technology has the potential as a disease-modifying therapy against AD to promote the degradation of amyloids, resulting in being comparable to immunotherapy. Here, we introduce our technology and its effects in vivo that we showed previously in Ozawa et al., Brain , 2021, as well as a further improvement towards non-invasive in vivo photo-oxygenation described in another publication Nagashima et al., Sci. Adv. , 2021, as expanded discussion

O-N intramolecular alkoxycarbonyl migration of typical protective groups in hydroxyamino acids

O-N Intramolecular alkoxycarbonyl (carbonate-carbamate) migration was found to occur as a common reaction of hydroxyamino acids under mild basic aqueous conditions with no formation of side products. Carbonate protective groups migrate to produce amino-protected carbamate derivatives of hydroxyamino acids with high efficiency and purity

"O-acyl isopeptide method" for peptide synthesis: Synthesis of forty kinds of "O-acyl isodipeptide unit" Boc-Ser/Thr(Fmoc-Xaa)-OH

The O-acyl isopeptide method has recently received attention as an efficient synthetic method for peptides. Herein, forty kinds of "O-acyl isodipeptide unit" Boc-Ser/Thr(Fmoc-Xaa)-OH (1-40) were effectively synthesized in two-steps without epimerization. The O-acyl isodipeptide units are important building blocks to enable the routine use of the O-acyl isopeptide method

Development of first photoresponsive prodrug of paclitaxel

A prodrug of paclitaxel which has a coumarin derivative conjugated to the amino acid moiety of isotaxel (O-acyl isoform of paclitaxel) has been synthesized. The prodrug was selectively converted to isotaxel by visible light irradiation (430 nm) with the cleavage of coumarin. Finally, paclitaxel was released by subsequent spontaneous O-N intramolecular acyl migration. (c) 2006 Elsevier Ltd. All rights reserved