Università degli Studi di Milano, Dipartimento di Chimica, Milano, Italy.
Department of Chemistry, Simon Fraser University, Burnaby, British Columbia, Canada.
PLoS One. 2018 Feb 28;13(2):e0193623. doi: 10.1371/journal.pone.0193623. eCollection 2018.
The rise of drug-resistant influenza A virus strains motivates the development of new antiviral drugs, with different structural motifs and substitution. Recently, we explored the use of a bicyclic (bicyclo[3.1.0]hexane) analogue of sialic acid that was designed to mimic the conformation adopted during enzymatic cleavage within the neuraminidase (NA; sialidase) active site. Given that our first series of compounds were at least four orders of magnitude less active than available drugs, we hypothesized that the new carbon skeleton did not elicit the same interactions as the cyclohexene frameworks used previously. Herein, we tried to address this critical point with the aid of molecular modeling and we proposed new structures with different functionalization, such as the introduction of free ammonium and guanidinium groups and ether side chains other than the 3-pentyl side chain, the characteristic side chain in Oseltamivir. A highly simplified synthetic route was developed, starting from the cyclopropanation of cyclopentenone and followed by an aziridination and further functionalization of the five-member ring. This allowed the efficient preparation of a small library of new bicyclic ligands that were characterized by enzyme inhibition assays against influenza A neuraminidases N1, its H274Y mutant, and N2. The results show that none of the new structural variants synthesized, including those containing guanidinium groups rather than free ammonium ions, displayed activity against influenza A neuraminidases at concentrations less than 2 mM. We conclude that the choice and positioning of functional groups on the bicyclo[3.1.0]hexyl system still need to be properly tuned for producing complementary interactions within the catalytic site.
耐药性流感 A 病毒株的出现促使人们开发新的抗病毒药物，这些药物具有不同的结构基序和取代基。最近，我们探索了使用一种双环（bicyclo[3.1.0]hexane）类似物的方法，该类似物设计用于模拟神经氨酸酶（NA；唾液酸酶）活性位点内酶切过程中采用的构象。鉴于我们的第一个系列化合物的活性至少比现有药物低四个数量级，我们假设新的碳骨架不会引起与以前使用的环己烯骨架相同的相互作用。在此，我们借助分子建模试图解决这一关键点，并提出了具有不同功能化的新结构，例如引入游离的铵和胍基以及除 3-戊基侧链之外的醚侧链，这是奥司他韦的特征侧链。我们开发了一种高度简化的合成路线，从环戊烯酮的环丙烷化开始，然后进行氮丙啶化，并进一步对五元环进行官能化。这使得能够高效制备新的二环配体的小文库，并用酶抑制测定法对流感 A 神经氨酸酶 N1、其 H274Y 突变体和 N2 进行了表征。结果表明，在所合成的新结构变体中，没有一种（包括含有胍基而不是游离铵离子的变体）在低于 2mM 的浓度下对流感 A 神经氨酸酶显示出活性。我们得出结论，对于在催化位点内产生互补相互作用，还需要适当调整双环[3.1.0]己基系统上的功能基团的选择和定位。
