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Effectiveness of some anti-HIV/AIDS drugs for 2019-nCoV

Lopinavir is an antiretroviral medication used to inhibit HIV/AIDS viral protease. It is often used as a fixed-dose combination with another protease inhibitor, ritonavir, sold under the name Kaletra or Aluvia. Ritonavir, sold under the trade name Norvir, is another antiretroviral medication. Its combination with Lopinavir is known as highly active antiretroviral therapy (HAART). Although there is no tractable clinical evidence, Kaletra or Aluvia has been proposed as a potential anticoronavirus drug for 2019-nCoV. The possibility of repurposing some HIV drugs for SARS-CoV treatment has also studied in the literature. 16 It is important to evaluate their binding affinities, which are obtained with two ligand-based methods (i.e., LS-BP and 2DFP) and two 3D models (3DALL and 3DMT). To carry out 3D model predictions, we dock them to the 2019-nCoV protease inhibition site. The resulting complexes are optimized with molecular dynamics and then evaluated by 3DALL and 3DMT. Table 1 shows the low sequence identity between HIV viral protease and 2019-nCoV protease, which might suggest the limited potential for repurposing Aluvia and Norvir for 2019-nCoV treatment. For Lopinavir, our LS-BP and 2DFP predicted the binding affinities of -5.66 kcal/mol and -5.54 kcal/mol, respectively. For Ritonavir, similar low binding affinities of -5.14 kcal/mol and -4.96 kcal/mol were predicted by our LS-BP and 2DFP, respectively. However, our 3D model 3DALL predicted better binding affinities, i.e., -7.78 kcal/mol and -8.44 kcal/mol for Lopinavir and Ritonavir, respectively. The other 3D model, 3DMT, also predicted moderately high binding affinities of -8.13 kcal/mol and -8.07 kcal/mol for Lopinavir and Ritonavir, respectively. Considering the fact that the small training set for LS-BP and 2DFP models is very small, the results predicted by 3D models are more reliable. Figures 20 and 21 indicate that these drugs have reasonable dock poses with 2019-nCoV protease. Therefore, HIV drugs Kaletra (or Aluvia) and Norvir might indeed have a moderate effect in the treatment of 2019-nCoV. However, Many new compounds generated by our GNC appear to have better druggable properties than these HIV inhibitors do. epidemic. Although we know quite a little about 2019-nCoV, it is fortunate that the sequence identity of the 2019-nCoV protease and that of severe acute respiratory syndrome virus (SARS-CoV) is as high as 96.1%. In this work, we show that the protease inhibitor binding sites of 2019-nCoV and SARS-CoV are almost identical, which provides a foundation for us to hypothesize that all potential anti-SARS-CoV chemotherapies are also effective anti-2019-CoV molecules. Additionally, we employed a recently developed generative network complex (GNC) to seek potential protease inhibitors for effective treatment of pneumonia caused by 2019-nCoV. Two datasets 13 . CC-BY-NC 4.0 International license author/funder. It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/2020.01.30.927889 doi: bioRxiv preprint are utilized in this work. One is a SARS-CoV protease inhibitor dataset, which is constructed by collecting 115 SRAS-CoV inhibitors from open database ChEMBL. The other dataset is a binding affinity training set mainly containing the PDBbind refined set. Our GNC model predicts over 8000 potential anti-2019-nCoV drugs which are evaluated by a latent space binding predictor (LS-BP) and a 2D fingerprint predictor (2DFP). Promising drug candidates are further evaluated by two 3D deep learning models trained with all the training sets together, including the dataset for coronaviral protease (3DALL), and the 3D deep learning multitask model trained with the dataset for coronaviral protease as a separated task (3DMT). Furthermore, we choose 15 potential anti-2019-nCoV drugs to analyze partition coefficient (logP), solubility (logS), and synthetic accessibility score (SAscore) according to binding affinity ranking computed by the 3DALL model. The reasonable logP, logS, and SAscore show that our top 15 anti-2019-nCoV drug candidates are potentially effective for inhibiting 2019-nCoV. Finally, the effectiveness of some anti-HIV/AIDS drugs for treating 2019-nCoV is analyzed. Although HIV drugs Kaletra (or Aluvia) and Norvir might indeed have a moderate effect in the treatment of 2019-nCoV, the analysis of these anti-HIV/AIDS drugs together with our top 15 anti-2019-nCoV molecules shows that the new compounds generated by our GNC appear to have better druggable properties than these HIV inhibitors do.
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Abstract

designed to target viral proteinases. However, in our prediction, they may also bind to the replication complex components of 2019-nCoV with an inhibitory potency with Kd < 1000 nM. In addition, we also found that several antiviral agents, such as Kaletra, could be used for the treatment of 2019-nCoV, although there is no real-world evidence supporting the prediction. Overall, we suggest that the list of antiviral drugs identified by the MT-DTI model should be considered, when establishing effective treatment strategies for 2019-nCoV.
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Background

Based on in vitro data, the combination of lopinavir and ritonavir has been considered as a candidate therapy for MERS. Lopinavir and ritonavir are antiretroviral protease inhibitors used in combination for the treatment of human immunodeficiency virus (HIV) infection and have limited side effects [20] . The combination of lopinavir/ritonavir (Kaletra®, Abbott Laboratories, Chicago, IL, USA) has also been used for the treatment of SARS. In one study, the combination of lopinavir/ritonavir used in 41 patients with SARS was associated with significantly fewer adverse clinical outcomes (acute respiratory distress syndrome or death) 21 days after the onset of symptoms compare to ribavirin alone used in 111 historical controls (2.4% versus 28.8%, p = 0.001) [21] . However, the historical nature of the control comparison does not allow for a valid estimate of efficacy. In a high-throughput screening for antiviral compounds, lopinavir inhibited the replication of MERS-CoV at levels below those that occur in the circulation after a single oral dose of lopinavir/ritonavir (400 mg lopinavir with 100 mg ritonavir), suggesting that the drug can achieve therapeutic levels in vivo [16, 22] . The effects of lopinavir/ritonavir, IFN-β1b and mycophenolate mofetil (MMF), all of which have shown viral inhibitory effects in vitro, have been tested in common marmosets with severe MERS-CoV infection [23] . The animals treated with lopinavir/ritonavir or IFN-β1b had improved clinical, radiological, pathological and viral-load outcomes compared with untreated animals. By contrast, treatment with MMF resulted in severe or fatal disease, with higher mean viral loads than in untreated animals. Untreated animals and MMF-treated animals had a mortality of 67% by 36 h compared to 0-33% among animals treated with lopinavir/ritonavir or IFN-β1b [23] .
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Introduction

The trial fifth edition of diagnosis and treatment guideline of COVID-19 issued by National Health Commission of the People's Republic of China (http://www.nhc.gov.cn/) recommends to use Kaletra for treatment. Kaletra, an anti-HIV drug which is composed of two protease inhibitors, ritonavir (CAS#: 155213-67-5) and lopinavir (CAS#: 192725-17-0), might have therapeutic effect on coronavirus diseases like SARS and MERS [7] [8] [9] [10] . However, whether it can inhibit SARS-CoV-2 or treat COVID-19 lacks clinical evidences and randomized clinical trials, and the safety of its use in COVID-19 patients is unclear. Otherwise, Lanjuan Li, infectious disease scientist, academician of Chinese Academy of Engineering, recommended darunavir (CAS#: 206361-99-1), also an HIV protease inhibitor, as a treatment for COVID-19. Although the inhibitory effect of darunavir on SARS-CoV-2 has been verified in vitro, its therapeutic effect on COVID-19 is still unknown. At the same time, the mechanism of how these drugs inhibit SARS-CoV-2 is also unknown.
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Therapeutics

Many interferons from the three classes have been tested for their antiviral activities against SARS-CoV both in vitro and in animal models. Interferon β has consistently been shown to be the most active, followed by interferon α. The use of corticosteroids with interferon alfacon-1 (synthetic interferon α) appeared to have improved oxygenation and faster resolution of chest radiograph abnormalities in observational studies with untreated controls. Interferon has been used in multiple observational studies to treat SARS-CoV and MERS-CoV patients [116, 117] . Interferons, with or without ribavirin, and lopinavir/ritonavir are most likely to be beneficial and are being trialed in China for 2019-nCoV. This drug treatment appears to be the most advanced. Timing of treatment is likely an important factor in effectiveness. A combination of ribavirin and lopinavir/ritonavir was used as a post-exposure prophylaxis in health care workers and may have reduced the risk of infection. Ribavirin alone is unlikely to have substantial antiviral activities at clinically used dosages. Hence, ribavirin with or without corticosteroids and with lopinavir and ritonavir are among the combinations employed. This was the most common agent reported in the available literature. Its efficacy has been assessed in observational studies, retrospective case series, retrospective cohort study, a prospective observational study, a prospective cohort study and randomized controlled trial ranging from seven to 229 participants [117] . Lopinavir/ritonavir (Kaletra) was the earliest protease inhibitor combination introduced for the treatment of SARS-CoV. Its efficacy was documented in several studies, causing notably lower incidence of adverse outcomes than with ribavirin alone. Combined usage with ribavirin was also associated with lower incidence of acute respiratory distress syndrome, nosocomial infection and death, amongst other favorable outcomes. Recent in vitro studies have shown another HIV protease inhibitor, nelfinavir, to have antiviral capacity against SARS-CoV, although it has yet to show favorable outcomes in animal studies [118] . Remdesivir (Gilead Sciences, GS-5734) nucleoside analogue in vitro and in vivo data support GS-5734 development as a potential pan-coronavirus antiviral based on results against several coronaviruses (CoVs), including highly pathogenic CoVs and potentially emergent BatCoVs. The use of remdesivir may be a good candidate as an investigational treatment.
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Treatment Situation and In-hospital Outcomes

There were 40 cases (97.6%) received at least one kind of antiviral drugs empirically including oseltamivir, ribavirin, arbidol or lopinavir/ritonavir (Kaletra), which were accessible clinically in China. Antibiotics or anti-fungus drugs were applied in 95.1% cases regarding to confirmed secondary infection or preventing secondary infection in relatively severe cases. Corticosteroid was used in 78.0% cases to control immune overreaction. Human albumin was applied when serum albumin . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
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Antiviral therapy

Lopinavir-ritonavir co-formulation (Kaletra ® , Abbott Laboratories, USA) is a protease inhibitor for the treatment of human immunodeficiency virus (HIV) infection. It can inhibit the coronaviral proteases, thus blocking the processing of viral replicase polyprotein and preventing the replication of viral RNA. Ritonavir inhibits lopinavir metabolism thus increasing its serum concentration, but it has no activity against SARS-CoV. In a retrospective analysis in Hong Kong [26] , 31 patients who had received Kaletra as rescue therapy together with high dose corticosteroids had no difference in rates of oxygen desaturation, intubation and mortality compared with a matched cohort. However, when given as initial treatment in combination with ribavirin in another subgroup of 44 patients, there were significant reductions in the need for rescue pulsed corticosteroid therapy, intubation rate and overall mortality. In addition to the prevalence of diarrhoea among these patients which may render oral drugs more appropriate and useful, synergism between kaletra and ribavirin might have contributed to the benefits since either drug alone has only weak anti-viral activities. Another Hong Kong study of 41 SARS patients treated with a combination of lopinavir/ritonavir and ribavirin compared with 111 patients (historical controls) treated with ribavirin only showed that adverse clinical outcomes (ARDS or death) were significantly lower in the treatment group than in the historical controls at day 21 after symptom onset. Further randomised placebo controlled trials are required [27] .