Abstract
Human parainfluenza viruses represent a leading cause of lower respiratory tract disease in children, with currently no available approved drug or vaccine. The viral surface glycoprotein haemagglutinin-neuraminidase (HN) represents an ideal antiviral target. Herein, we describe the first structure-based study on the rearrangement of key active site amino acid residues by an induced opening of the 216-loop, through the accommodation of appropriately functionalised neuraminic acid-based inhibitors. We discovered that the rearrangement is influenced by the degree of loop opening and is controlled by the neuraminic acid’s C-4 substituent’s size (large or small). In this study, we found that these rearrangements induce a butterfly effect of paramount importance in HN inhibitor design and define criteria for the ideal substituent size in two different categories of HN inhibitors and provide novel structural insight into the druggable viral HN protein.
Highlights
Human parainfluenza virus is one of the leading causes of respiratory tract disease in infants and children[1, 2] and is estimated to result in over 1.5 million cases per year in the United States alone[3]
This study demonstrated that the protein forms a covalent adduct with the substrate as a result of a nucleophilic attack at the neuraminic acid (Neu) moiety’s anomeric carbon (C-2) by the hydroxyl group of the key catalytic amino acid, Tyr[530]
To accommodate the C-4 substituents of each inhibitor, the respective 216-loop[11] was forced into a more open conformation in each complex when compared with the apo structure (PDB accession code: 4XJQ)
Summary
Human parainfluenza virus (hPIV) is one of the leading causes of respiratory tract disease in infants and children[1, 2] and is estimated to result in over 1.5 million cases per year in the United States alone[3]. This study demonstrated that the protein forms a covalent adduct with the substrate as a result of a nucleophilic attack at the Neu moiety’s anomeric carbon (C-2) by the hydroxyl group of the key catalytic amino acid, Tyr[530] It was verified[9] that hPIV-3 HN can be targeted by reactive substrate-like inhibitors such as 4. We have recently described the design and synthesis of novel potent 4-deoxy-4-triazolo-Neu2en-based inhibitors (5 and 6, Fig. 1)[10] These inhibitors carry bulky C-4 substituents on the Neu2en template and target the proposed 216-cavity formed by movement of the flexible 216-loop[11], a unique feature in hPIV-3 HN. Taken together these developments inspired further structural and biological investigation of Neu (1)-based inhibitors that incorporate a C-5 isobutyramido moiety, bulky C-4 triazole-substituents and C-2 and C-3 fluorides, such as 7 and 8, to evaluate functional group synergism
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
