Drug repurposing based on a quantum-inspired method versus classical fingerprinting uncovers potential antivirals against SARS-CoV-2

Abstract

The COVID-19 pandemic has accelerated the need to identify new antiviral therapeutics at pace, including through drug repurposing. We employed a Quadratic Unbounded Binary Optimization (QUBO) model, to search for compounds similar to Remdesivir, the first antiviral against SARS-CoV-2 approved for human use, using a quantum-inspired device. We modelled Remdesivir and compounds present in the DrugBank database as graphs, established the optimal parameters in our algorithm and resolved the Maximum Weighted Independent Set problem within the conflict graph generated. We also employed a traditional Tanimoto fingerprint model. The two methods yielded different lists of lead compounds, with some overlap. While GS-6620 was the top compound predicted by both models, the QUBO model predicted BMS-986094 as second best. The Tanimoto model predicted different forms of cobalamin, also known as vitamin B12. We then determined the half maximal inhibitory concentration (IC50) values in cell culture models of SARS-CoV-2 infection and assessed cytotoxicity. We also demonstrated efficacy against several variants including SARS-CoV-2 Strain England 2 (England 02/2020/407073), B.1.1.7 (Alpha), B.1.351 (Beta) and B.1.617.2 (Delta). Lastly, we employed an in vitro polymerization assay to demonstrate that these compounds directly inhibit the RNA-dependent RNA polymerase (RdRP) of SARS-CoV-2. Together, our data reveal that our QUBO model performs accurate comparisons (BMS-986094) that differed from those predicted by Tanimoto (different forms of vitamin B12); all compounds inhibited replication of SARS-CoV-2 via direct action on RdRP, with both models being useful. While Tanimoto may be employed when performing relatively small comparisons, QUBO is also accurate and may be well suited for very complex problems where computational resources may limit the number and/or complexity of possible combinations to evaluate. Our quantum-inspired screening method can therefore be employed in future searches for novel pharmacologic inhibitors, thus providing an approach for accelerating drug deployment.

Identification of CD8 T-cell dysfunction associated with symptoms in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and Long COVID and treatment with a nebulized antioxidant/anti-pathogen agent in a retrospective case series

“…These patients appeared to be self-reporting significant improvement while on treatment. This treatment, as outlined above, has ingredients that would relieve oxidative stress ( Maes et al, 2011 , 2012a , 2012b , 2021 ; Dennis et al, 2021 ; Kumar et al, 2020 ; Wu, 2020 ; Al-Hakeim et al, 2023 ; Fukuda et al, 1994 ; Paul et al, 2021 ; Takemoto et al, 2021 ; Gould et al, 2010 , 2011 , 2015 ; Prousky, 2007 ; Rusznak et al, 2000 ; Buhl et al, 1990 ; Dekhuijzen, 2004 ; Straface et al, 2000 ; Bridgeman et al, 1991 ; Hagiwara et al, 2000 ; Paulin et al, 2017 ; Lima et al, 2013 ; Juergens et al, 2003 , 2004 , 2018 , 2020 ; Rhoden et al, 2004 ; Kennedy-Feitosa et al, 2016 ; Dahham et al, 2015 ; Machado et al, 2018 ; Kim et al, 2015 ), known to be disturbed in ME/CFS and Long COVID; attenuate NF-κB signaling ( Kim et al, 2015 ; Greiner et al, 2013 ; Francomano FC et al, 2019 ; Oka et al, 2000 ; Sudhoff et al, 2015 ; Yadav and Chandra, 2017 ; Cantin et al, 2000 ; Lou and Kaplowitz, 2007 ; Xu et al, 2016 ), which would decrease T-cell receptor (TCR) signaling and potentially reverse CD8 T-cell dysfunction; and act directly against pathogens, including viruses, bacteria and fungi ( Dahham et al, 2015 ; Holroyd et al, 1993 ; Nencioni et al, 2003 ; Roederer et al, 1990 ; Geiler et al, 2011 ; Yang et al, 2010 ; Li et al, 2016 ; Astani et al, 2011 ; Pajaro-Castro et al, 2015 ; Cavar Zeljkovic et al, 2022 ; Kim et al, 2022 ; Jimenez-Guard...…”

“…All the components in this nebulized agent have been reported to have broad direct anti-viral properties against several viruses, including several that routinely produce respiratory symptoms, including parainfluenza-1, influenza A (H5N1), herpes simplex virus type-1 (HSV-1) and type-2 (HSV-2), human immune deficiency virus (HIV-1), and dengue virus 2 (DENV-2) ( Holroyd et al, 1993 ; Nencioni et al, 2003 ; Roederer et al, 1990 ; Geiler et al, 2011 ; Yang et al, 2010 ; Li et al, 2016 ; Astani et al, 2011 ; Pajaro-Castro et al, 2015 ). 1,8-cineole, β-caryophyllene and methylcobalamin each have antiviral properties to SARS-CoV-2 ( Cavar Zeljkovic et al, 2022 , Jimenez-Guardeno et al, 2022 , Kim et al, 2022 ). β-caryophyllene has broad spectrum antibacterial properties (in vitro) against several bacterial species, including S. aureus, K. pneumoniae, and P. aeruginosa, and in vivo for M .…”

Inactivated Poliovirus Vaccine Booster Reduces the Likelihood of COVID-19 Outcomes in Individuals Primed with Oral Poliovirus Vaccination

“…Overall, 282 participants (age, median [range], 55 [ 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , …”

“…For instance, remdesivir, an intravenous RdRp inhibitor developed for the Ebola virus, and molnupiravir, an oral drug designed for the influenza virus, are commonly used to treat symptomatic COVID-19 patients [ 17 , 18 , 19 , 20 ]. Since in silico (computer simulations), in vitro (laboratory experiments), and in vivo (studies performed on living organisms) evidence has demonstrated the efficacy of RdRp inhibitors against SARS-CoV-2 variants, it is unsurprising that these drugs have been successful across the various waves of SARS-CoV-2 strains [ 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 ]. In addition to the exploration of RdRp inhibitors as COVID-19 disease treatments, there has also been interest in using anti-RdRp agents in a prophylactic manner (i.e., to prevent disease and/or provide some protection before an exposure may occur).…”

Rationale and Experience of Vitamin B12 Usage in Complex Therapy of COVID-19 and Post-COVID Syndrome

“…Достаточное потребление витамина B12 необходимо и для производства антител и клональной экспансии [17,21,39], а его дефицит связан с более низкими концентрациями циркулирующих лимфоцитов и измененными ответами на основе антител [40].…”