1989 Fiscal Year Final Research Report Summary
Design and Synthesis of Novel Inhibitors Modeled on Plant Protease Inhibitors
| Project/Area Number |
63470023
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| Research Category |
Grant-in-Aid for General Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
天然物有機化学
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| Research Institution | Kyushu University |
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Principal Investigator |
WAKI Michinori Kyushu University, Faculty of Science, Research Associate, 理学部, 助手 (30037212)
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| Co-Investigator(Kenkyū-buntansha) |
AOYAGI Haruhiko Kyushu University, Faculty of Science, Associate Professor, 理学部, 助教授 (80037267)
OHNO Motonori Kyushu University, Faculty of Science, Professor, 理学部, 教授 (30038434)
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| Project Period (FY) |
1988 – 1989
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| Keywords | Protease inhibitor / Plant inhibitor / Trypsin inhibitory peptide / Chymotrypsin inhibitory peptide / Peptide synthesis |
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| Research Abstract |
To search and develop a novel potent protease inhibitor, a reactive-site peptide of soybean Bowman-Birk inhibitor (BBI) with dual inhibitory activities against trypsin (Tsin) and chymotrypsin (Csin) was selected as structural bases. 1. Reactive-site peptides of BBI: A parent nonapeptide of the anti-Tsin domain of BBI, in which the P_1 site is Lys for Tsin inhibitor (la) or Tyr for Csin inhibitor (1b), and the nonapeptide analog (2a or 2b) of 1, in which the scissile reactive-site dipeptide is replaced by uncleavable statine-type isostere (3a or 3b) derived from Lys or Tyr, were devised as synthetic targets. (1) Isosteres: Effective synthetic route for diastereomeric 3 from L-amino acid was established. (2) Tsin or Csin inhibition: Only one diastereomer (3S,4S)-3a or (3S,4S)-2b inhibited Tsin or Csin weakly, indicating that the specific stereochemistry of the isosteric residue is required for the activity-exhibition. By contrast, the parent 1b was the most potent Csin-inhibitor (Ki=1.2 x 10^<-7> M) among the BBI-related synthetic peptides. 2. Reactive-site peptides of peanut inhibitor B-III: BBI-type nonapeptide (4) and B-III-type undecapeptide (5) with the reactive-site of B-III were synthesized. 5 inhibited both Tsin and Csin, while 4 only Tsin, indicating that the undecapeptide-structure of 5 is a minimum constituent to exhibit the B-III activity. 3. Csin-inhibitory dipeptides: A series of dipeptides with sterically constrained dehydro or methanophenylalanine and related simple dipeptides were designed and synthesized. Evaluation of the inhibitory activities and conformational analysis suggest the backbone structure of the Csin- inhibitory dipeptides to be in a specific inhibitory conformation. Such structure may become an important unit in designing of more effective inhibitors.
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