Discovery of N-Substituted Oseltamivir Derivatives as Potent and Selective Inhibitors of H5N1 Influenza Neuraminidase

Abstract

To discover group-1-specific neuraminidase (NA) inhibitors that are especially involved in combating the H5N1 virus, two series of oseltamivir derivatives were designed and synthesized by targeting the 150-cavity. Among these, compound 20l was the most potent N1-selective inhibitor, with IC50 values of 0.0019, 0.0038, and 0.0067 μM against NAs from three H5N1 viruses. These values are better than those of oseltamivir carboxylate. Compound 32 was another potent N1-selective inhibitor that exhibited a 12-fold increase in activity against the H274Y mutant relative to oseltamivir carboxylate. Molecular docking studies revealed that the 150-cavity was an auxiliary binding site that may contribute to the high selectivity of these compounds. The present work is a significant breakthrough in the discovery of potent group-1-specific neuraminidase inhibitors, which may be further investigated for the treatment of infection by the H5N1 virus.

Structure-Based Optimization of N-Substituted Oseltamivir Derivatives as Potent Anti-Influenza A Virus Agents with Significantly Improved Potency against Oseltamivir-Resistant N1-H274Y Variant

“…28 Our own previous research focused on exploiting the 150-cavity led to the identification of a series of N-substituted 6 oseltamivir derivatives with low nanomolar N1-selective inhibitory activity against NAs from three H5N1 viruses. 17 It is noteworthy that, compared with OSC, the two most potent compounds 5 and 6 (group-1-specific NA inhibitors in Figure 3A) showed about 3-9 times greater inhibitory potency against three H5N1 NA subtypes. However, compound 5 did not show improved activity against the H5N1-H274Y mutant as compared to OSC (5, IC = 1.16 μM; OSC, IC 50 = 2.1 μM).…”

“…NAs by a factor of more than 100, 17,18 leading to clinical failure of oral oseltamivir. 15,19,20 Therefore, discovery of new drugs active against oseltamivir-resistant strains, especially those with H274Y, is becoming increasingly urgent.…”

“…But, interestingly, 6 showed a 12-fold increase in activity against this mutant relative to OSC (IC 50 = 0.16 μM), supporting the idea that addition of substituents to the oseltamivir core could result in stronger interactions with the 150-cavity, restoring affinity for the H274Y mutant. 17 (B) Key residues that may interact with 5. 17 Our previous structure-activity relationships (SARs) study and molecular modeling indicated that some of the highest-affinity 150-cavity binders interact primarily through hydrophobic interactions.…”

QSAR and molecular mechanism analysis of N-substituted oseltamivir derivatives as potent avian influenza H5N1 neuraminidase inhibitors

“…Activity of N-substituted oseltamivir derivatives against influenza H5N1 virus were taken from reference [35]. IC 50 values were transformed by pIC 50 = -lg (IC 50 ).…”

Molecular docking analysis of N-substituted oseltamivir derivatives with the SARS-Cov-2 main protease

“…Among the drugs proposed as antiviral agents of COVID-19, we selected Oseltamivir [2,5]. To date, oseltamivir has been the first choice as an effective treatment for infections with influenza A and B, and has been widely used since its approval in 1999 [6]. Many papers reported the effect of chloroquine and hydroxy chloroquine in the treatment of COVID-…”