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15 pages, 4253 KiB

Open AccessArticle

SKGQA, a Peptide Derived from the ANA/BTG3 Protein, Cleaves Amyloid-β with Proteolytic Activity

by Yusuke Hatakawa, Rina Nakamura, Toshifumi Akizawa, Motomi Konishi, Akira Matsuda, Tomoyuki Oe, Motoaki Saito and Fumiaki Ito

Biomolecules 2024, 14(5), 586; https://doi.org/10.3390/biom14050586 - 15 May 2024

Cited by 1 | Viewed by 1609

Abstract

Despite the extensive research conducted on Alzheimer’s disease (AD) over the years, no effective drug for AD treatment has been found. Therefore, the development of new drugs for the treatment of AD is of the utmost importance. We recently reported the proteolytic activities of JAL-TA9 (YKGSGFRMI) and ANA-TA9 (SKGQAYRMA), synthetic peptides of nine amino acids each, derived from the Box A region of Tob1 and ANA/BTG3 proteins, respectively. Furthermore, two components of ANA-TA9, ANA-YA4 (YRMI) at the C-terminus end and ANA-SA5 (SKGQA) at the N-terminus end of ANA-TA9, exhibited proteolytic activity against amyloid-β (Aβ) fragment peptides. In this study, we identified the active center of ANA-SA5 using AEBSF, a serine protease inhibitor, and a peptide in which the Ser residue of ANA-SA5 was replaced with Leu. In addition, we demonstrate the proteolytic activity of ANA-SA5 against the soluble form Aβ42 (a-Aβ42) and solid insoluble form s-Aβ42. Furthermore, ANA-SA5 was not cytotoxic to A549 cells. These results indicate that ANA-SA5 is a promising Catalytide and a potential candidate for the development of new peptide drugs targeting Aβ42 for AD treatment. Full article

(This article belongs to the Special Issue Amyloid-Beta and Alzheimer’s Disease)

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9 pages, 2881 KiB

Open AccessArticle

Structure–Activity Relationship of 5-mer Catalytides, GSGYR and RYGSG

by Rina Nakamura, Toshifumi Akizawa and Motomi Konishi

Biomolecules 2022, 12(12), 1766; https://doi.org/10.3390/biom12121766 - 27 Nov 2022

Cited by 4 | Viewed by 1710

Abstract

We recently discovered JAL-TA9 (YKGSGFRMI), a short hydrolytic peptide that we termed a Catalytide. The catalytic center of JAL-TA9 was modeled using MM2 and MMFF94 parameters and identified as GSGFR. Additionally, a structure–activity relationship study showed that GSGYR cleaved Aβ11-29. Here, we developed a novel Catalytide in silico. Molecular dynamics simulations of GSGYR and RYGSG using MM2 and MMFF94 parameters suggested that both peptides may form catalytic triads and oxyanion holes. The hydrolytic potency of RYGSG was five times higher than that of GSGYR. Moreover, both peptides showed three common cleavage positions for Aβ11-29; namely, L17-V18, V18-F19, and E22-D23. The aggregation ratio analyzed by the thioflavin-T assay correlated well with proteolytic activity, suggesting that the aggregation of Aβ11-29 was suppressed by the cleavage reaction. Docking simulations with the carbonyl carbon of L17 or the carbonyl carbon of E22 in Aβ11-29 were conducted using the secondary structures of GSGYR and RYGSG. The distance between the hydroxyl group of serine and the carbonyl carbon of the two cleavage sites proved that RYGSG was closer to Aβ11-29 than to GSGYR. This study demonstrated that Catalytides are useful for understanding structure–activity relationships. Full article

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13 pages, 2005 KiB

Open AccessArticle

Direct Delivery of ANA-TA9, a Peptide Capable of Aβ Hydrolysis, to the Brain by Intranasal Administration

by Yusuke Hatakawa, Akiko Tanaka, Tomoyuki Furubayashi, Rina Nakamura, Motomi Konishi, Toshifumi Akizawa and Toshiyasu Sakane

Pharmaceutics 2021, 13(10), 1673; https://doi.org/10.3390/pharmaceutics13101673 - 13 Oct 2021

Cited by 8 | Viewed by 2532

Abstract

We have recently reported Catalytides (Catalytic peptides) JAL-TA9 (YKGSGFRMI) and ANA-TA9 (SKGQAYRMI), which are the first Catalytides found to cleave Aβ42. Although the Catalytides must be delivered to the brain parenchyma to treat Alzheimer’s disease, the blood–brain barrier (BBB) limits their entry into the brain from the systemic circulation. To avoid the BBB, the direct route from the nasal cavity to the brain was used in this study. The animal studies using rats and mice clarified that the plasma clearance of ANA-TA9 was more rapid than in vitro degradation in the plasma, whole blood, and the cerebrospinal fluid (CSF). The brain concentrations of ANA-TA9 were higher after nasal administration than those after intraperitoneal administration, despite a much lower plasma concentration after nasal administration, suggesting the direct delivery of ANA-TA9 to the brain from the nasal cavity. Similar findings were observed for its transport to CSF after nasal and intravenous administration. The concentration of ANA-TA9 in the olfactory bulb reached the peak at 5 min, whereas those in the frontal and occipital brains was 30 min, suggesting the sequential backward translocation of ANA-TA9 in the brain. In conclusion, ANA-TA9 was efficiently delivered to the brain by nasal application, as compared to other routes. Full article

(This article belongs to the Special Issue Nose to Brain Delivery (Volume II))

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