Sialidase Inhibitors with Different Mechanisms

Abstract

Sialidases, or neuraminidases, are enzymes that catalyze the hydrolysis of sialic acid (Sia)-containing molecules, mostly removal of the terminal Sia (desialylation). By desialylation, sialidase can modulate the functionality of the target compound and is thus often involved in biological pathways. Inhibition of sialidases with inhibitors is an important approach for understanding sialidase function and the underlying mechanisms and could serve as a therapeutic approach as well. Transition-state analogues, such as anti-influenza drugs oseltamivir and zanamivir, are major sialidase inhibitors. In addition, difluoro-sialic acids were developed as mechanism-based sialidase inhibitors. Further, fluorinated quinone methide-based suicide substrates were reported. Sialidase product analogue inhibitors were also explored. Finally, natural products have shown competitive inhibiton against viral, bacterial, and human sialidases. This Perspective describes sialidase inhibitors with different mechanisms and their activities and future potential, which include transition-state analogue inhibitors, mechanism-based inhibitors, suicide substrate inhibitors, product analogue inhibitors, and natural product inhibitors.

Figure 1

Sialic acids (Sias) and their linkages, cell surface sialylation and desialylation by sialidases.

Figure 2

Catalytic mechanism of the hydrolytic sialidase with net retention of the anomeric configuration. (A) First step, Tyr residue acts as a nucleophile to attach the anomeric center (C-2), (B) semiplanar oxocarbenium transition state formation with the adjacent carbohydrate attached, (C) covalent intermediate that is bound to the active site, (D) another semiplanar oxocarbenium transition state formation with a water molecule attached, and (E) finally, release of free Sia as an α-anomer.

Figure 3

Transition-state analogue sialidase inhibitors in different scaffolds. IC₅₀ values are for influenza viral NA inhibition. (A) Influenza neuraminidase inhibitors with pyran scaffold, (B) influenza neuraminidase inhibitors with carbocyclic scaffold, (C) selective sialidase inhibitors by modifying C-4, -5, -7, and -9 positions, and (D) sialidase inhibitors with other kinds of scaffolds.

Figure 4

Transition-state analogue bacterial sialidase inhibitors with modification at C-9 and C-5 position of DANA. (a) Neu5Gc9N₃2en, (b) 9-Triazole-linked and 5-N-trifluoroacetyl derivative of DANA, and (c) 9-triazole-linked peptide derivatives of DANA.

Scheme 1. Sialidase-Catalyzed Reaction with Mechanism-Based Inhibitor 2,3-diF-Neu5Ac in Glycosylation (k₁) and Deglycosylation (k₂) Steps

Figure 5

(a) Fluorinated quinone methide-based suicide substrate sialidase inhibitors and their covalent inhibition mechanism and (b) macrocycle-based suicide substrate sialidase inhibitor.

Figure 6

Phosphonic acid and sulfo acid analogues of Sia as product analogue sialidase inhibitors.

Figure 7

Structures of 2,7-anhydro-Neu5Ac (1) and its derivatives 2–4..

Figure 8

Natural product bacterial sialidase inhibitors. (a) siastatin B, (b) 7-(3,4-dihydroxyphenyl)-5-hydroxy-1-(3-hydroxy-4-methoxyphenyl) hepta-1,4,6-trien-3-one, (c) evernic acid, (d) prenylated isoflavone, (e) chromenone, (f) artocarpin, (g) diplacone, and (h) katsumadain A.

Figure 9

Natural product protozoan sialidase inhibitor, (a) 6-chloro-9,10-dihydro-4,5,7-trihydroxy-9,10-dioxo-2-anthracenecarboxylic acid and human sialidase inhibitors, (b) Feddeiketone B, (c) 2,3-dihydroxy-1-(4-hydroxy-3,5-dimethoxyphenyl)-l-propanone, and (d) syringylglycerol.