Construction of a small peptide library related to inhibitor om99-2 and its structure-activity relationship to β-secretase

ABSTRACT AIM: To develop probes for detecting the binding specificity between β-secretase and substrate, and provide reliable biological activity data for further researching encircling

substrate-based inhibitors. METHODS: To prepare the inhibitors, the hydroxyethylene (HE) segment including P1 and P1′ was synthesized after multi-step reactions; the combination of all

segments was then completed through solid phase synthesis. Recombinant human β-secretase ectodomain (amino acid residues 1-460) was expressed as a secreted protein with a C-terminal His tag

in insect cells using baculovirus infection, and all compounds were evaluated in this β-secretase enzyme assay. In order to understand the interaction in detail, the theoretical methods,

namely molecular dynamics (MD) simulation and molecular mechanics-generalized-born surface area (MM-GBSA) analysis, were performed on the complex of β-secretase and OM99-2 to obtain the

geometrical and energetical information. RESULTS: We designed and constructed a positional scanning combinatorial library including 16 compounds; all members of the library were synthesized

based on HE dipeptide isostere. Structure-activity relationship studies at the P4-P1 and P1′-P4′ positions led to the discoveries of P and P′ sides binding specificity and potent inhibitors

14, 18, and 22. The binding free energy on the whole system and every residue were compared to the biological assay result. CONCLUSION: The removal of P4′ yielded inhibitor 22 (A3*B2) with

high potency; further truncation of P3′ gave inhibitor 18 (A3*B1) with equal activity, implying that the right side of the inhibitors play a less important role and could be easily

simplified, while change on the P side may cause substantial results. SIMILAR CONTENT BEING VIEWED BY OTHERS IN VITRO SELECTION OF MACROCYCLIC PEPTIDE INHIBITORS CONTAINING CYCLIC Γ2,4-AMINO

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references AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * State Key Laboratory of Drug Research and National Center for Drug Screening, Shanghai Institute of Materia Medica, Shanghai

Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 201203, China Bin Hu, Bing Xiong, Bei-ying Qiu, Xin Li, Hai-ping Yu, Kun Xiao, Xin Wang, Jia Li & Jing-kang

Shen Authors * Bin Hu View author publications You can also search for this author inPubMed Google Scholar * Bing Xiong View author publications You can also search for this author inPubMed 

Google Scholar * Bei-ying Qiu View author publications You can also search for this author inPubMed Google Scholar * Xin Li View author publications You can also search for this author

inPubMed Google Scholar * Hai-ping Yu View author publications You can also search for this author inPubMed Google Scholar * Kun Xiao View author publications You can also search for this

author inPubMed Google Scholar * Xin Wang View author publications You can also search for this author inPubMed Google Scholar * Jia Li View author publications You can also search for this

author inPubMed Google Scholar * Jing-kang Shen View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Jing-kang Shen.

ADDITIONAL INFORMATION Project supported by the National Natural Science Foundation of China (No 30230400 and 30200341) and the State Key Program of Basic Research of China (2004GB 518907).

RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Hu, B., Xiong, B., Qiu, By. _et al._ Construction of a small peptide library related to inhibitor OM99-2

and its structure-activity relationship to β-secretase. _Acta Pharmacol Sin_ 27, 1586–1593 (2006). https://doi.org/10.1111/j.1745-7254.2006.00432.x Download citation * Received: 15 April

2006 * Accepted: 19 June 2006 * Issue Date: 01 December 2006 * DOI: https://doi.org/10.1111/j.1745-7254.2006.00432.x SHARE THIS ARTICLE Anyone you share the following link with will be able

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initiative KEYWORDS * β-secretase * hydroxyethylene * OM99-2 * Alzheimer's disease * structure-activity relationship