A vimentin-targeting oral compound with host-directed antiviral and anti-inflammatory actions addresses multiple features of COVID-19 and related diseases

Abstract

Damage in COVID-19 results from both the SARS-CoV-2 virus and its triggered overreactive host immune responses. Therapeutic agents that focus solely on reducing viral load or hyperinflammation fail to provide satisfying outcomes in all cases. Although viral and cellular factors have been extensively profiled to identify potential anti-COVID targets, new drugs with significant efficacy remain to be developed. Here, we report the potent preclinical efficacy of ALD-R491, a vimentin-targeting small molecule compound, in treating COVID-19 through its host-directed antiviral and anti-inflammatory actions. We found that by altering the physical properties of vimentin filaments, ALD-491 affected general cellular processes as well as specific cellular functions relevant to SARS-CoV-2 infection. Specifically, ALD-R491 reduced endocytosis, endosomal trafficking, and exosomal release, thus impeding the entry and egress of the virus; increased the microcidal capacity of macrophages, thus facilitating the pathogen clearance; and enhanced the activity of regulatory T cells, therefore suppressing the overreactive immune responses. In cultured cells, ALD-R491 potently inhibited the SARS-CoV-2 spike protein and human ACE2-mediated pseudoviral infection. In aged mice with ongoing, productive SARS-CoV-2 infection, ALD-R491 reduced disease symptoms as well as lung damage. In rats, ALD-R491 also reduced bleomycin-induced lung injury and fibrosis. Our results indicate a unique mechanism and significant therapeutic potential for ALD-R491 against COVID-19. We anticipate that ALD-R491, an oral, fast-acting, and non-toxic agent targeting the cellular protein with multipart actions, will be convenient, safe, and broadly effective, regardless of viral mutations, for patients with early- or late-stage disease, post-COVID complications and other related diseases.

Research and development of Chinese anti-COVID-19 drugs

“…The in vivo studies suggested that ALD-R491 significantly reduces the lung damage and fibrosis. The above results indicate that ALD-R491 can be used to treat COVID-19 and can also reduce the recurrence due to its effects on the prevention and treatment of lung damage 11 .…”

“…ALD-R491 exerts antiviral and anti-inflammatory dual effects by targeting vimentin. Vimentin has a role in the entry, intracellular transport, and release of the virus, as well as an inflammatory response 11 . ALD-R491 can reduce endocytosis, endosomal transport and exosome release, thus preventing the virus from entering or leaving cells.…”

A snapshot of protein trafficking in SARS‐CoV‐2 infection

“…The importance of endosomal morphology and function for SARS-CoV-2 entry was demonstrated in a study reporting alteration of intermediate filaments (IF) to affect both entry and egress steps of SARS-CoV-2 (Li et al, 2021c) (Figure 1). Using the pharmacological inhibitor ALD-491 targeting the class III IF vimentin, the authors reported reduced SARS-CoV-2 entry and exosomal release in cell culture-based assays as well as mitigated disease severity and lung damage in aged mice.…”

“…Infection alters the architecture of the ER and the network of DMVs was found to be surrounded by a ‘cage‐like’ vimentin network and pharmacological inhibition of intermediate filaments with Withaferin A reduced SARS‐CoV‐2 replication (Cortese et al., 2020). Of note, vimentin appears to have a dual role in the SARS‐CoV‐2 infection cycle, by contributing to viral entry (see section ‘ENDOSOMAL TRAFFICKING AND SARS‐COV‐2 ENTRY’, Figure 1) and egress of infectious virus particles (Li et al., 2021c). It has been shown that newly assembled ß‐coronaviruses exit the cells using lysosomal exocytosis with lysosomes being deacidified and lysosomal enzymes inactivated (Ghosh et al., 2020).…”