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2.
Clinical Cancer Research ; 27(6 SUPPL 1), 2021.
Article in English | EMBASE | ID: covidwho-1816903

ABSTRACT

Vimentin intermediate filament is involved in multiple steps of viral infection such as viral entry, trafficking and egress, as well as in various mechanisms of hyperinflammation such as the restraint of Treg cell functions and the activation of NLRP3 inflammasome. We evaluated a vimentin-binding small molecule compound ALD-R491 for its effects on cellular processes related to viral infection and for its efficacy in treating SARS-CoV2 infection in vitro and in vivo. In cultured cells, the compound could reduce endocytosis by 10%, endosomal trafficking by 40% and exosomal release by over 30%. In an infection system consisting of a lentiviral pseudotype bearing the SARS-CoV-2 spike protein and HEK293 cells over-expressing the human ACE2 receptor with multiplicity of infection (MOI) of 1, 10 and 100, the compound inhibited the infection up to a maximum of over 90%, with IC 50 < 50 nM, CC50 > 10 μM, and SI > 200. After oral administration of ALD-R491 in rats, the plasma concentration of the compound reached the peak (Tmax) at around 5 h with a half-life (T1/2) of about 5 h. The compound was widely distributed and enriched in tissues in vivo in rats with a volume of distribution (Vd) of over 2,000 ml/kg. The lung and the lymph nodes were among the tissues with high drug exposures. In rats receiving oral gavage of the compound at 30 mg/kg, the drug exposure in the lung and the lymph nodes maintained at levels over 1 μM from 1 h to 6 h after the oral dosing. In the syngeneic mouse tumor CT26 model, ALD-R491 was found to activate regulatory T cells (Tregs) in vivo and enhance de novo generation of Tregs in lymph nodes of the mice. In the Mouse-Adapted SARS-CoV2 model, aged mice (11-12 months) were used to provide a harder test of recovery from infection that reflects the severeness of COVID-19 in old patients. For therapeutic treatment, the mice were orally administered with the compound 24 h after the SARS-CoV2 infection once per day on Day 1, Day 2 and Day 4. At 10 mg/kg, ALD-R491 significantly reduced the body weight loss of the mice (p<0.01 on Day 5 post-infection). At both 3 mg/kg and 10 mg/kg, the compound significantly reduced the hemorrhagic score for the lungs (p<0.01 and p<0.05, respectively, on Day 5). These results indicate that vimentin intermediate filament is an effective host-directed antiviral target. Importantly, the vimentin-binding small molecule ALD-R491 impacts multiple aspects of SARS-CoV2 infection, has a favorable oral pharmacokinetics and a wide therapeutic window, and therefore may be a promising therapeutic candidate for treating COVID-19. Statement: Aluda Pharmaceuticals, Inc. has utilized the non-clinical and pre-clinical services program offered by the National Institute of Allergy and Infectious Diseases.

3.
American Journal of Respiratory and Critical Care Medicine ; 203(9), 2021.
Article in English | EMBASE | ID: covidwho-1277575

ABSTRACT

RATIONALE While SARS-CoV-2 viral infection, acute lung injury, and inflammation resolve in a timely manner in most individuals, there is growing clinical evidence of long-term sequelae of COVID-19 in some patients, particularly in vulnerable populations. We established a mouse model of SARS-CoV-2 infection using a mouseadapted virus and a standard laboratory strain of mice that displays age-dependent disease severity. In comparison to young BALB/c mice, old BALB/c mice display increased morbidity and mortality when infected with SARS-CoV-2 MA-10, and most succumb to acute infection or reach the criteria for humane euthanasia within 7 days of infection. We examined the lung pathology of older BALB/c mice that survive acute infection to determine the potential long-term pulmonary manifestations of COVID-19 in vulnerable populations such as the elderly.METHODS Mice were randomized and assigned to specific harvest days spanning 30 days prior to the start of the experiment. BALB/cAnNHsd mice were intranasally infected with SARS-CoV-2 MA-10 and clinical signs of disease were monitored, including weight loss and lung function via whole body plethysmography. At each time point, animals were sacrificed and lung lobes were collected for viral titer and histopathological analyses. Lung viral titers of the caudal right lobe were determined by plaque assay. Histopathology of the left lobe was assessed utilizing formalin-fixed, paraffin-embedded specimens.RESULTSIn comparison to 10-week-old BALB/c mice, 1-year-old BALB/c mice were highly susceptible to SARS-CoV-2 MA-10, displaying high morbidity and mortality, even requiring a lower viral dose than young BALB/c mice to yield similar kinetics of weight loss and clinical signs. In some experiments, survival of older mice was low as ∼15% at day 7. For older mice surviving to days 15 and 30 post infection, acute lung injury resolved but there were regionally extensive consolidated areas containing proliferative smooth muscle actin-positive fibroblasts, collagen accumulation, and admixed immune cells with formation of tertiary lymphoid organs. Mice displaying this pulmonary fibroproliferative response did not have detectable levels of virus in the lung.CONCLUSIONSThis mouse adapted SARS-CoV-2 model reveals a response in older mice surviving acute lung injury with robust chronic inflammation and tissue remodeling resulting in pulmonary fibrosis despite viral clearance of the tissue. This offers a model to investigate mediators driving the fibroproliferative and inflammatory responses that may be a COVID-19 sequela and cause persistent pulmonary dysfunction in some vulnerable patients such as the elderly.

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