Assessment of repurposed compounds against coronaviruses highlights the antiviral broad-spectrum activity of host-targeting iminosugars and confirms the activity of potent directly acting antivirals

Article

Author: Makower, Laetitia L ; Zitzmann, Nicole ; Rangel, Victor ; Alonzi, Dominic S ; Hill, Michelle L ; Kiappes, J L ; Dwek, Raymond A ; von Delft, Annette ; Gileadi, Carina ; Brun, Juliane ; Arman, Benediktus Yohan ; Witt, Karolina D

The COVID-19 pandemic highlights the need for novel antiviral drug discovery approaches that could dramatically shorten timelines from compound discovery to clinical development. At the beginning of the pandemic, repurposing approaches were at the forefront of early research efforts to screen for antiviral activity against SARS-CoV-2 in over 2500 compounds. Here, we report cellular screening results of 100 FDA-approved and experimental compounds against SARS-CoV-2 in the human Calu-3 cell line. We observed 13 compounds showing antiviral activity against SARS-CoV-2, including seven FDA-approved compounds (remdesivir, boceprevir, amiloride, nafamostat, cisplatin, silmitasertib, and miglustat), and six compounds in pre-clinical and clinical development (tarloxotinib, lucerastat (NB-DGJ), MON-DNJ, NAP-DNJ, NN-DGJ and NN-DNJ). Further, we observed that our screening hits include several host-targeting antivirals, namely iminosugars, that are largely non-toxic and offer a large therapeutic window. The most-developed iminosugar MON-DNJ (UV-4B), which has been evaluated in a Phase 1 clinical trial, shows antiviral activity against SARS-CoV-2 wild type as well as alpha, beta, gamma, delta, and Omicron variants. Its activity also extended to another betacoronavirus HCoV OC43, but not alphacoronavirus HCoV 229E. Our cellular screening results add to the body of knowledge on antivirals against coronaviruses and confirm the antiviral efficacy of iminosugars in cellular assays using the human lung-cell line Calu-3.

01 Jan 2024·Biochimica et Biophysica Acta (BBA) - Biomembranes

Repurposing dye ligands as antivirals via a docking approach on viral membrane and globular proteins – SARS-CoV-2 and HPV-16

Review

Author: Wang, Chia-Wen ; Chen, Yi-Ming ; Lu, Ching-Tai ; Fischer, Wolfgang B

A series of dye ligands are docked to three different proteins, E and 3a of severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) and E6 of human papilloma virus type 16 (HPV-16) using three different software. A four-level selection algorithm is used based on nonparametric statistics of numerical key values such as the "rank" derived from (i) averaged estimated binding energies (EBEs) and (ii) absolute EBE value of each of the software, (iii) frequency of ranking and (iv) rank of the area-under-curve values (AUCs) from decoy docking. A series of repurposing drugs and known antivirals used in experimental studies are docked for comparison. One dye ligand is ranked best for all proteins using the selection algorithm levels i - iii. Another three dye ligands are ranked top for the proteins individually when using all four levels.

01 Apr 2023·Biomedicine & Pharmacotherapy

N-butyldeoxynojirimycin (miglustat) ameliorates pulmonary fibrosis through inhibition of nuclear translocation of Smad2/3

Article

Author: Murayama, Toshihiko ; Kasahara, Junya ; Yamazaki, Risa ; Nakamura, Hiroyuki ; Watanabe, Kazuaki ; Kurumiya, Eon ; Sakamoto, Yuka ; Zhou, Yuan ; Takabatake, Mamoru ; Hayashi, Kyota ; Tatsumi, Koichiro ; Honda, Takuya ; Yamazaki, Ayako ; Kasuya, Yoshitoshi ; Yoshino, Ichiro

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease. The disease involves excessive accumulation of fibroblasts and myofibroblasts, and myofibroblasts differentiated by pro-fibrotic factors promote the deposition of extracellular matrix proteins such as collagen and fibronectin. Transforming growth factor-β1 is a pro-fibrotic factor that promotes fibroblast-to-myofibroblast differentiation (FMD). Therefore, inhibition of FMD may be an effective strategy for IPF treatment. In this study, we screened the anti-FMD effects of various iminosugars and showed that some compounds, including N-butyldeoxynojirimycin (NB-DNJ, miglustat, an inhibitor of glucosylceramide synthase (GCS)), a clinically approved drug for treating Niemann-Pick disease type C and Gaucher disease type 1, inhibited TGF-β1-induced FMD by inhibiting the nuclear translocation of Smad2/3. N-butyldeoxygalactonojirimycin having GCS inhibitory effect did not attenuate the TGF-β1-induced FMD, suggesting that NB-DNJ exerts the anti-FMD effects by GCS inhibitory effect independent manner. N-butyldeoxynojirimycin did not inhibit TGF-β1-induced Smad2/3 phosphorylation. In a mouse model of bleomycin (BLM)-induced pulmonary fibrosis, intratracheal or oral administration of NB-DNJ at an early fibrotic stage markedly ameliorated lung injury and deterioration of respiratory functions, such as specific airway resistance, tidal volume, and peak expiratory flow. Furthermore, the anti-fibrotic effects of NB-DNJ in the BLM-induced lung injury model were similar to those of pirfenidone and nintedanib, which are clinically approved drugs for the treatment of IPF. These results suggest that NB-DNJ may be effective for IPF treatment.

100 Deals associated with N-nonyldeoxynojirimycin

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Indication	Highest Phase	Country/Location	Organization	Date
Hepatitis B	Phase 1	-	Thomas Jefferson University	-
Hepatitis B	Phase 1	-	University of Oxford	-
Hepatitis B	Phase 1	-	Pfizer Inc.	-
Hepatitis B	Phase 1	-	Synergy Pharmaceuticals LLC	-
Hepatitis C	Phase 1	-	Synergy Pharmaceuticals LLC	-
Hepatitis C	Phase 1	-	Pfizer Inc.	-
Hepatitis C	Phase 1	-	Thomas Jefferson University	-
Hepatitis C	Phase 1	-	University of Oxford	-

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