Mechanism-Based Covalent Neuraminidase Inhibitors with Broad-Spectrum Influenza Antiviral Activity

Abstract

Influenza antiviral agents play important roles in modulating disease severity and in controlling pandemics while vaccines are prepared, but the development of resistance to agents like the commonly used neuraminidase inhibitor oseltamivir may limit their future utility. We report here on a new class of specific, mechanism-based anti-influenza drugs that function through the formation of a stabilized covalent intermediate in the influenza neuraminidase enzyme, and we confirm this mode of action with structural and mechanistic studies. These compounds function in cell-based assays and in animal models, with efficacies comparable to that of the neuraminidase inhibitor zanamivir and with broad-spectrum activity against drug-resistant strains in vitro. The similarity of their structure to that of the natural substrate and their mechanism-based design make these attractive antiviral candidates.

Investigating the Influence of (Deoxy)fluorination on the Lipophilicity of Non‐UV‐Active Fluorinated Alkanols and Carbohydrates by a New log P Determination Method

“…However,o ur determination that as hift of approximately 0.65 log P is maintained for the much more lipophilic 29, an ovel compound, shows that the actual b-trifluorination effect is independent of the absolute log P value.D ouble b-trifluorination, as in 7 and 15,c auses as ignificant log P increase.Pentafluorinated substrates (13,20,24,and 36)show af urther increase in lipophilicity.I nterestingly,t he DDlog P value for the corresponding trifluorinated derivatives is strongly dependent on whether the pentafluoroethyl group is in the a-position of the alcohol group or not (12/13, 18/20 vs.…”

“…Fluorinated carbohydrates find application as mechanism-based inhibitors, [20] for the stabilization of glycosidic bonds, [21] and have historically also been used as probes for sugar epitope mapping. [22] Briefly,adecreased binding affinity upon monodeoxyfluorination indicates ah ydrogen bond (HB) donor function for the replaced alcohol, whereas as imilar binding affinity suggests that it functions as an HB acceptor.H owever,i ti sd ifficult to take the altered lipophilicity of fluorinated carbohydrates into account in binding data interpretations,i np art because there are no quantitative data regarding the influence of deoxyfluorination on carbohydrate lipophilicity.G iven the difficult quantification of carbohydrate concentrations,a sw ell as the fact that the clog P values for diastereomeric sugars are identical, these substrates were deemed an ideal test case to demonstrate the usefulness of our log P determination method, taking into account that the fluorine signals of both anomers, and possibly the furanose forms,n eed to be integrated.…”

Trapping influenza neuraminidase

“…1 The new molecules are being developed by CDRD Ventures Inc., the venture arm of The Centre for Drug Research and Development, a public-private partnership that commercializes discoveries from Canadian researchers.…”

Glycoprofiling as a novel tool in serological assays of systemic sclerosis: A comparative study with three bioanalytical methods

“…Moreover, in this study three different bioanalytical approaches for glycoprofiling of human sera are described, including traditional ELISA-like method enzyme-linked lectin assay (ELLA), novel multiplexed lectin microarray format of analysis and ultrasensitive EIS-based biosensing with immobilized lectins. Since glycosylation is the most common posttranslational modification of proteins (≥50% of all eukaryotic proteins and ≥70% of all therapeutic proteins) [19,32] a huge scientific effort is devoted to better understanding of their role in cell processes or to apply such knowledge to design better therapeutics or diagnostic tools [33][34][35][36][37][38][39][40]. Thus, glycoprofiling of samples from SSc patients can be an alternative way for future early stage diagnostics of the SSc disease and other diseases including various types of cancer associated with aberrant glycosylation.…”