VP1 crystal structure-guided exploration and optimization of 4,5-dimethoxybenzene-based inhibitors of rhinovirus 14 infection

International audienceHuman rhinoviruses (HRV) are the predominant cause of common colds and flu-like illnesses, but are also responsible for virus-induced exacerbations of asthma and chronic obstructive pulmonary disease. However, to date, no drug has been approved yet for clinical use. In this study, we present the results of the structure-based lead optimization of a class of new small-molecule inhibitors that we previously reported to bind into the pocket beneath the canyon of the VP1 protein. A small series of analogues that we designed based on the available structure and interaction data were synthesized and evaluated for their potency to inhibit the replication of HRV serotype 14. 2-(4,5-Dimethoxy-2-nitrophenyl)-1-(4-(pyridin-4-yl)phenyl)ethanol (3v) was found to be a potent inhibitor exhibiting micromolar activity (EC50 = 3.4 ± 1.0 μM) with a toxicity for HeLa cells that was significantly lower than that of our previous hit (LPCRW_0005, CC50 = 104.0 ± 22.2 μM; 3v, CC50 > 263 μM)

Heterocyclic pharmacochemistry of new rhinovirus antiviral agents: a combined computational and experimental study

Rhinovirus (RV)​, member of the Enterovirus genus, is known to be involved in more than half of the common colds. Through advances in mol. biol., rhinoviruses have also been assocd. with exacerbations of chronic pulmonary diseases (e.g., asthma, chronic obstructive pulmonary disease (COPD) and cystic fibrosis)​. In the current investigation, the authors develop a novel series of 4,​5-​dimethoxybenzyl derivs. that potently inhibits rhinovirus replication. Compd. (S)​-​7f ((S)​-​1-​(4-​(1H-​pyrazol-​4-​yl)​phenyl)​-​2-​(4,​5-​dimethoxy-​2-​nitrophenyl)​ethanol) blocks RV-​B14 replication with an EC50 value of 0.25 μM and shows a low toxicity in HeLa cells (CC50 > 271 μM)​. Enantiosepn. followed by an abs. configuration detn. by a Mosher's method revealed the interest of enantiopure compds. Mol. docking studies permitted the identification of key biol. interactions within the drug-​binding pocket and an in silico drug-​like study revealed a good potential for the development of these derivs

Direct comparison of the in vitro and in vivo stability of DFO, DFO* and DFOcyclo* for 89 Zr-immunoPET

International audiencePurpose Currently, the most commonly used chelator for labelling antibodies with 89 Zr for immunoPET is desferrioxamine B (DFO). However, preclinical studies have shown that the limited in vivo stability of the 89 Zr-DFO complex results in release of 89 Zr, which accumulates in mineral bone. Here we report a novel chelator DFOcyclo*, a preorganized extended DFO derivative that enables octacoordination of the 89 Zr radiometal. The aim was to compare the in vitro and in vivo stability of [ 89 Zr]Zr-DFOcyclo*, [ 89 Zr]Zr-DFO* and [ 89 Zr]Zr-DFO. Methods The stability of 89 Zr-labelled chelators alone and after conjugation to trastuzumab was evaluated in human plasma and PBS, and in the presence of excess EDTA or DFO. The immunoreactive fraction, IC 50 , and internalization rate of the conjugates were evaluated using HER2-expressing SKOV-3 cells. The in vivo distribution was investigated in mice with subcutaneous HER2 + SKOV-3 or HER2 − MDA-MB-231 xenografts by PET/CT imaging and quantitative ex vivo tissue analyses 7 days after injection. Results 89 Zr-labelled DFO, DFO* and DFOcyclo* were stable in human plasma for up to 7 days. In competition with EDTA, DFO* and DFOcyclo* showed higher stability than DFO. In competition with excess DFO, DFOcyclo*-trastuzumab was significantly more stable than the corresponding DFO and DFO* conjugates (p < 0.001). Cell binding and internalization were similar for the three conjugates. In in vivo studies, HER2 + SKOV-3 tumour-bearing mice showed significantly lower bone uptake (p < 0.001) 168 h after injection with [ 89 Zr]Zr-DFOcyclo*-trastuzumab (femur 1.5 ± 0.3%ID/g, knee 2.1 ± 0.4%ID/g) or [ 89 Zr]Zr-DFO*-trastuzumab (femur 2.0 ± 0.3%ID/g, knee 2.68 ± 0.4%ID/g) than after injection with [ 89 Zr]Zr-DFO-trastuzumab (femur 4.5 ± 0.6%ID/g, knee 7.8 ± 0.6%ID/g). Blood levels, tumour uptake and uptake in other organs were not significantly different at 168 h after injection. HER2 − MDA-MB-231 tumour-bearing mice showed significantly lower tumour uptake (p < 0.001) after injection with [ 89 Zr]Zr-DFOcyclo*-trastuzumab (16.2 ± 10.1%ID/g) and [ 89 Zr]Zr-DFO-trastuzumab (19.6 ± 3.2%ID/g) than HER2 + SKOV-3 tumour-bearing mice (72