Selective Bias Virtual Screening for Discovery of Promising Antimalarial Candidates targeting Plasmodium N-Myristoyltransferase.

Malaria remains a significant public health challenge, with Plasmodium vivax being the species responsible for the most prevalent form of the disease. Given the limited therapeutic options available, the search for new antimalarials against P. vivax is urgent. This study aims to identify new inhibitors for P. vivax N-myristoyltransferase (PvNMT), an essential drug target against malaria. Through a validated virtual screening campaign, we prioritized 23 candidates for further testing. In the yeast NMT system, seven compounds exhibit a potential inhibitor phenotype. In vitro antimalarial phenotypic assays confirmed the activity of four candidates while demonstrating an absence of cytotoxicity. Enzymatic assays reveal LabMol-394 as the most promising inhibitor, displaying selectivity against the parasite and a strong correlation within the yeast system. Furthermore, molecular dynamics simulations shed some light into its binding mode. This study constitutes a substantial contribution to the exploration of a selective quinoline scaffold and provides valuable insights into the development of new antimalarial candidates.

Flavonoids from Pterogyne nitens as Zika virus NS2B-NS3 protease inhibitors.

Although the widespread epidemic of Zika virus (ZIKV) and its neurological complications are well-known there are still no approved drugs available to treat this arboviral disease or vaccine to prevent the infection. Flavonoids from Pterogyne nitens have already demonstrated anti-flavivirus activity, although their target is unknown. In this study, we virtually screened an in-house database of 150 natural and semi-synthetic compounds against ZIKV NS2B-NS3 protease (NS2B-NS3p) using docking-based virtual screening, as part of the OpenZika project. As a result, we prioritized three flavonoids from P. nitens, quercetin, rutin and pedalitin, for experimental evaluation. We also used machine learning models, built with Assay Central® software, for predicting the activity and toxicity of these flavonoids. Biophysical and enzymatic assays generally agreed with the in silico predictions, confirming that the flavonoids inhibited ZIKV protease. The most promising hit, pedalitin, inhibited ZIKV NS2B-NS3p with an IC50 of 5 µM. In cell-based assays, pedalitin displayed significant activity at 250 and 500 µM, with slight toxicity in Vero cells. The results presented here demonstrate the potential of pedalitin as a candidate for hit-to-lead (H2L) optimization studies towards the discovery of antiviral drug candidates to treat ZIKV infections.

A diarylamine derived from anthranilic acid inhibits ZIKV replication.

Zika virus (ZIKV) is a mosquito-transmitted Flavivirus, originally identified in Uganda in 1947 and recently associated with a large outbreak in South America. Despite extensive efforts there are currently no approved antiviral compounds for treatment of ZIKV infection. Here we describe the antiviral activity of diarylamines derived from anthranilic acid (FAMs) against ZIKV. A synthetic FAM (E3) demonstrated anti-ZIKV potential by reducing viral replication up to 86%. We analyzed the possible mechanisms of action of FAM E3 by evaluating the intercalation of this compound into the viral dsRNA and its interaction with the RNA polymerase of bacteriophage SP6. However, FAM E3 did not act by these mechanisms. In silico results predicted that FAM E3 might bind to the ZIKV NS3 helicase suggesting that this protein could be one possible target of this compound. To test this, the thermal stability and the ATPase activity of the ZIKV NS3 helicase domain (NS3Hel) were investigated in vitro and we demonstrated that FAM E3 could indeed bind to and stabilize NS3Hel.