Taurultam shows antiviral activity against SARS-CoV-2 and influenza virus

Abstract

Background: SARS-CoV-2 and influenza virus are highly contagious respiratory viruses that continuously pose major threats to human and public health. The high frequency of viral mutations led to the emergence of resistant isolates and caused virus epidemics repeatedly, emphasizing the urgent need to develop new antivirals. Taurultam is a metabolite of taurolidine. Moreover, taurolidine has been shown to have potent antiviral activities against multiple viruses and to have antiviral effects through its metabolites.

Results: In this study, we sought to determine the antiviral activities of taurultam against SARS-CoV-2 and influenza virus in Vero-E6, Huh7, 293T-ACE2, and MDCK cell lines and mouse infection models. The results showed that taurultam exhibited potent antiviral activity against multiple SARS-CoV-2 variants, influenza A (H1N1, H3N2) virus and influenza B virus, in vitro. Moreover, in influenza A (H1N1) virus, influenza B virus and SARS-CoV-2 infection models, taurultam significantly reduced viral loads, increased survival, improved mouse body weight and lung injury. Surprisingly, taurultam treatment not only inhibited the influenza A virus and SARS-CoV-2, but also benefited for therapy of mixed infection of these two viruses in vitro, demonstrating the great antiviral potential of taurultam for the treatment of SARS-CoV-2 and influenza virus infections.

Conclusions: Together, our findings identify taurultam as a new candidate for the treatment of SARS-CoV-2 and influenza virus infections, especially virus-induced lung pathology.

Clinical trial number: Not applicable.

Keywords: Antiviral; Influenza virus; Lung injury; SARS-CoV-2; Taurolidine metabolite; Taurultam.

Fig. 1

Taurultam shows potent antiviral activity against different SARS-CoV-2 variants in vitro. (A) Chemical formula of taurultam. (B) Effects of taurultam on the activity of (B) Vero-E6, (C) Huh7, and (D) 293T cells in a series of concentrations. (C) The inhibitory effects of taurultam on (E) SARS-CoV-2/BJ01, (F) Delta, (G) XBB 1.9.1, and (H) BF.7 in the Vero-E6 cell line. (D-E) Taurultam decreased the number of viral RNA copies of SARS-CoV-2/BJ01, Delta, XBB 1.9.1, and BF.7 in the cell supernatants of the (D) Vero-E6 and (E) Huh7 cell lines. (F-H) The inhibitory effects of taurultam (30 µg/mL) and molnupiravir (20 µg/mL) on (F-G) NP protein expression and (H) viral RNA copy numbers of SARS-CoV-2 in the 293T-ACE2 cell line. Scale bars = 50 μm

Fig. 2

Taurultam protects mice and golden hamsters from nonlethal and lethal SARS-CoV-2 infection in vivo. (A) Flow chart of the mouse experiment. (B) Effects of taurultam on the body weights of mice infected with the SARS-CoV-2/C57MA14 strain. (C) Taurultam improved mouse survival. (D) Lung tissues of the mice from each group and the respective histopathological results (HE staining) and immunohistochemical results (viral NP staining) of the lung tissue sections. (E-G) Lung indices, pathology scores and NP-positive cell populations of lung tissues from the mice in each group. (H) Viral RNA copy numbers in mouse lung tissues and turbinates. (I) Flow chart of the in vivo experiments involving golden hamsters. (J) Effects of taurultam on the body weight of golden hamsters infected with the BA.2 strain. (K) Viral RNA copy numbers in nasal lavage fluid samples from golden hamsters. (L) Lung tissues of golden hamsters from each group and respective histopathological results (HE staining) of lung tissue sections. (M-N) Lung indices and pathology scores of the lung tissues of golden hamsters from each group. (O) Viral RNA copy numbers in lung tissues, turbinates and trachea from golden hamsters

Fig. 3

Taurultam resists multiple Omicron variant infections in mouse models. (A-C) Lung indices and viral RNA copy numbers in the lung tissues and turbinates of BALB/c mice infected with Omicron BA.2. (D-F) Lung indices and viral RNA copy numbers in the lung tissues and turbinates of BALB/c mice infected with Omicron BF.7. (G-I) Lung indices and viral RNA copy numbers in the lung tissues and turbinates of C57BL/6 N mice infected with Omicron BF.7. (J-L) Lung indices and viral RNA copy numbers in the lung tissues and turbinates of BALB/c mice infected with XBB 1.9.1

Fig. 4

Taurultam inhibits influenza A virus and influenza B virus in vitro and in vivo. (A-D) Effects of Taurultam on the viral NP protein expression of (A, B) H1N1-UI182 and (C, D) IBV/S9-E2 in the MDCK cell line. Scale bars = 200 μm (E) Effects of Taurultam on the virus titres of H1N1-UI182 and IBV/S9-E2 in MDCK cell supernatants. (F) Effects of taurultam on the formation of plaques induced by H1N1-UI182 and IAV/H3N2. (G) Sizes of plaques from three biological replicates were measured in ImageJ software. For in vitro experiment, taurultam was used at 30 µg/mL and oseltamivir acid was used at 100 µM (H-I) Effects of taurultam on the (H) body weight and (I) survival rate of H1N1-UI182 strain-infected mice. (J) Lung tissues of mice from each group infected with H1N1-UI182 and the respective histopathological results (HE staining) of lung tissue sections. (K-L) Lung indices and pathology scores of lung tissues from H1N1-UI182-infected mice in each group. (M-N) Effects of taurultam on the (M) body weight and (N) survival rate of mice infected with the IBV/S9-MD strain. (O) Lung tissues of mice from each group infected with IBV/S9-MD and the respective histopathological results (HE staining) of lung tissue sections. (P-Q) Lung indices and pathology scores of lung tissues from mice in each group infected with IBV/S9-MD

Fig. 5

Taurultam benefit for the treatment of coinfection with influenza A virus and SARS-CoV-2. (A) Flow chart of the coinfection experiment. (B) Effect of taurultam on the survival rate of BALB/c mice coinfected with H1N1-UI182 and SARS-CoV-2/C57MA14. (C) Lung tissues of mice from each group infected with H1N1-UI182 and the respective histopathological results (HE staining) of lung tissue sections at 2 dpi and 4 dpi. (D) Pathology scores of the lung tissues of the mice in each group. (E-F) Effects of taurultam on the viral loads of SARS-CoV-2 and H1N1 in mouse turbinates at 2 dpi and 4 dpi. (G) Effects of taurultam on the body weight of golden hamsters coinfected with H1N1-UI182 and Omicron BF.7. (H) Lung tissues of golden hamsters and histopathological results (HE staining) of lung tissue sections at 3 dpi. (I-J) Lung indices and pathology scores of lung tissues from golden hamsters in each group