Antiviral Cystine Knot α-Amylase Inhibitors from Alstonia scholaris.

Abstract

Cystine knot α-amylase inhibitors are cysteine-rich, proline-rich peptides found in the Amaranthaceae and Apocynaceae plant species. They are characterized by a pseudocyclic backbone with two to four prolines and three disulfides arranged in a knotted motif. Similar to other knottins, cystine knot α-amylase inhibitors are highly resistant to degradation by heat and protease treatments. Thus far, only the α-amylase inhibition activity has been described for members of this family. Here, we show that cystine knot α-amylase inhibitors named alstotides discovered from the Alstonia scholaris plant of the Apocynaceae family display antiviral activity. The alstotides (As1-As4) were characterized by both proteomic and genomic methods. All four alsotides are novel, heat-stable and enzyme-stable and contain 30 residues. NMR determination of As1 and As4 structures reveals their conserved structural fold and the presence of one or more cis-proline bonds, characteristics shared by other cystine knot α-amylase inhibitors. Genomic analysis showed that they contain a three-domain precursor, an arrangement common to other knottins. We also showed that alstotides are antiviral and cell-permeable to inhibit the early phase of infectious bronchitis virus and Dengue infection, in addition to their ability to inhibit α-amylase. Taken together, our results expand membership of cystine knot α-amylase inhibitors in the Apocynaceae family and their bioactivity, functional promiscuity that could be exploited as leads in developing therapeutics.

• Authors: Phuong Quoc Thuc Nguyen, Justin Seng Geap Ooi, Ngan Thi Kim Nguyen, Shujing Wang, Mei Huang, Ding Xiang Liu, James P Tam
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 290 Issue 52 Pg. 31138-50 (Dec 25 2015) ISSN: 1083-351X [Electronic] United States
• PMID: 26546678 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Chemical References

• Antiviral Agents
• Glycoside Hydrolase Inhibitors
• Plant Proteins

Topics

• Alstonia (chemistry, genetics)
• Animals
• Antiviral Agents (chemistry, isolation & purification, pharmacology)
• Chlorocebus aethiops
• Coronavirus Infections (drug therapy, metabolism)
• Dengue
• Dengue Virus
• Glycoside Hydrolase Inhibitors (chemistry, isolation & purification, pharmacology)
• Infectious bronchitis virus (drug effects, metabolism)
• Plant Proteins (chemistry, genetics, isolation & purification, pharmacology)
• Protein Structure, Tertiary
• Vero Cells