Rota Paola, La Rocca Paolo, Bonfante Francesco, Pagliari Matteo, Cirillo Federica, Piccoli Marco, Ghiroldi Andrea, Franco Valentina, Pappone Carlo, Allevi Pietro, Anastasia Luigi
Department of Biomedical, Surgical and Dental Sciences, Università degli Studi di Milano, 20133 Milan, Italy.
Institute for Molecular and Translational Cardiology, San Donato Milanese, 20097 Milan, Italy.
ACS Med Chem Lett. 2023 Sep 26;14(10):1383-1388. doi: 10.1021/acsmedchemlett.3c00291. eCollection 2023 Oct 12.
In the search for effective antivirals against Paramyxoviridae, the dynamics of human parainfluenza virus type 1 hemagglutinin-neuraminidase (hPIV1-HN) inhibition offers a promising perspective. This study focuses on the potential of C5- and C4-modified 2,3-unsaturated sialic acid (DANA) inhibitors and highlights their interaction with the hPIV1-HN enzyme. We show that a strategic substitution, replacing the C5 isopropyl group in BCX 2798 with a trifluoroacetyl function, increases inhibitory potency 3- to 4-fold. At the same time, we explore the special properties of the catalytic site of hPIV1-HN, which harbors only small substituents and favors a C4 sulfonylamido function over a carbonyl function, in contrast to the C4 pocket of Newcastle disease virus hemagglutinin-neuraminidase (NDV-HN). Based on these findings, we present a newly identified potent inhibitor that has the preferred C5 trifluoroacetamido and C4 trifluorosulfonylamide groups. The results of this study pave the way for a deeper understanding of the C4 and C5 binding pockets of hPIV1-HN and promote the development of new, more selective inhibitors.
在寻找针对副粘病毒科的有效抗病毒药物的过程中，人副流感病毒1型血凝素-神经氨酸酶（hPIV1-HN）抑制作用的动力学提供了一个有前景的研究方向。本研究聚焦于C5和C4修饰的2,3-不饱和唾液酸（DANA）抑制剂的潜力，并突出了它们与hPIV1-HN酶的相互作用。我们发现，将BCX 2798中的C5异丙基用三氟乙酰基进行策略性取代，可使抑制效力提高3至4倍。同时，我们探究了hPIV1-HN催化位点的特殊性质，该位点仅含有小的取代基，与新城疫病毒血凝素-神经氨酸酶（NDV-HN）的C4口袋相比，更倾向于C4磺酰胺基功能而非羰基功能。基于这些发现，我们提出了一种新鉴定的强效抑制剂，其具有优选的C5三氟乙酰胺基和C4三氟磺酰胺基。本研究结果为更深入了解hPIV1-HN的C4和C5结合口袋铺平了道路，并促进了新型、更具选择性的抑制剂的开发。
