Exploring Human Parainfluenza Virus Type-1 Hemagglutinin–Neuraminidase as a Target for Inhibitor Discovery

Abstract

Human parainfluenza virus type 1 is the major cause of croup in infants and young children. There is currently neither vaccine nor clinically effective treatment for parainfluenza virus infection. Hemagglutinin-neuraminidase glycoprotein is a key protein in viral infection, and its inhibition has been a target for 2-deoxy-2,3-didehydro-d-N-acetylneuraminic acid (Neu5Ac2en)-based inhibitor development. In this study, we explore the effect of C-5 modifications on the potency of Neu5Ac2en derivatives that target the human parainfluenza type-1 hemagglutinin-neuraminidase protein. Our study demonstrates that the replacement of the Neu5Ac2en C-5 acetamido moiety with more hydrophobic alkane-based moieties improves the inhibitory potency for both hemagglutinin-neuraminidase functions. These findings shed light on the importance of C-5 substitution on Neu5Ac2en in the design of novel sialic acid-based inhibitors that target human parainfluenza type-1 hemagglutinin-neuraminidase.

Potent Inhibitors against Newcastle Disease Virus Hemagglutinin‐Neuraminidase

“…Along this line, we planned the synthesis of sulfonamide 2 a , via an azido intermediate. However, considering that some azido derivatives, such as BCX‐2798 1 b , have been reported among the most promising inhibitors against hPIVs, we also planned to synthesize the free azido compound 3 a . Additionally, we designed the synthesis of some unreported inhibitors, 2 b – d and 3 b – d , by combining the new selected C4 substituents ( p ‐toluenesulfonyl amido and azido) with the linear homologues perfluoracylamides at C5, from trifluoroacetic to heptafluorobutyric, that we previously reported .…”

“…After these preliminary considerations, we synthesized the p ‐toluenesulfonyl amido derivative 2 a and the azido compound 3 a . These selected molecules were achieved, according to the previously reported literature . However, the final hydrolytic step was performed with K 2 CO 3 in methanol/water (10:1) mixture, affording the desired inhibitors 2 a and 3 a in acidic form.…”

“…To this purpose, we synthesized some new analogues 2 b – d and 3 b – d . The key azido derivatives 8 b – d were obtained, as reported in Scheme , starting from compound 7 by direct N ‐transacylation of the amidic function at C5. Notably, these results highlighted that the N ‐transacylation reaction works well even in the presence of a relatively unstable azido group.…”

Oxidative Deamination ofN-Acetyl Neuraminic Acid: Substituent Effects and Mechanism

“…1-4 Modification of the amido group at the 5-position of N -amidoneuraminic acid derivatives has proved to be beneficial in the development of sialidase inhibitors and of carbohydrate antigens with greater antigenicity. 5-9 Such modifications have typically been achieved by N -deacetylation, its glycosides and derivatives, followed by reinstallation of different acyl groups, 6-7,10-12 or by use of the biosynthetic machinery when various N -acyl mannosamines are converted enzymatically to the corresponding N -acyl neuraminic acids 13 and eventually their glycosides, 14-15 or by a combination of the biosynthetic and chemical methods. 16 Consequently, modifications are typically limited to amide derivatives or other simple substitutions that are compatible with the biosynthetic machinery such as the conversion of 2-deoxy glucose to 5-desacetamido neuraminic acid.…”

The Catalytic Mechanism of Human Parainfluenza Virus Type 3 Haemagglutinin‐Neuraminidase Revealed

“…To investigate the catalytic mechanism of hPIV-3 HN, the 2,3-difluoro analogues (3-5) of the previously reported potent hPIV inhibitor BCX2798 (2), have been synthesized following the procedures illustrated in Figure 1 b. The synthesis of the target compounds started with the known [21,22] 4-azido-4deoxy-5-isobutyramido-Neu2en intermediate 6. The halohydrins 7 and 8 were obtained in very good overall yields of 58 % and 35 %, respectively, and in a short period of time by heating intermediate 6 with Selectfluor in an aqueous nitromethane solution by microwave (MW) irradiation for 2 h at 80 8C.…”