Anti-SARS and anti-HCV drugs repurposing against the Papain-like protease of the newly emerged coronavirus (2019-nCoV)

doi:10.21203/rs.2.23280/v1

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Anti-SARS and anti-HCV drugs repurposing against the Papain-like protease of the newly emerged coronavirus (2019-nCoV)

https://doi.org/10.21203/rs.2.23280/v1

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A new mysterious coronavirus outbreak started last month in China. The World Health Organization (WHO) termed the new virus strain 2019-nCoV to be the seventh reported human coronaviruses (HCoV). A seafood market in Wuhan city, central China was the starting point of the emergence with unknown animal causes the first animal to human infection. Until today 904 confirmed deaths and more than 40000 cases confirmed in China and 28 countries. There is a massive fear of the human to human transmission of 2019-nCoV that reported last week by the Chinese government. The most famous two strains of HCoV are the Severe Acute Respiratory Syndrome coronavirus (SARS CoV) and the Middle East Respiratory Syndrome coronavirus (MERS CoV). The former had emerged in China in 2002 while the latter emerged in the Middle East region in 2012 and south Korea in 2015. In this study, the newly emerged 2019-nCoV papain-like protease (PL^pro) is targeted by anti-SARS PL^pro drugs and the anti-Hepatitis C Virus (HCV) Non-structural protein 3 (NS3) serine protease drugs. Sequence analysis, modeling, and docking are used to get a valid model for 2019-nCoV PL^pro. The results suggest the effectiveness of the anti-SARS drugs (GRL-0667, GRL-0617, and Mycophenolic acid) and the anti-HCV drugs (Grazoprevir, Telaprevir, and Boceprevir) as potent inhibitors against the newly emerged coronavirus.

Biophysics

Infectious Diseases

Wuhan coronavirus

2019-nCoV PLpro

docking

Grazoprevir

Telaprevir

drug repurposing

A New emerged human coronavirus (2019-nCoV) is reported last month in Wuhan city in China ^1,2. According to the World Health Organization (WHO) surveillance draft two weeks ago, any traveler to Wuhan, Hubei Province in China, 15 days before the onset of the symptoms, is suspected to be a 2019-nCoV patient ^2,3. Additionally, WHO distributed interim guidance for laboratories that carry out the tests for the emerged outbreak and it releases infection prevention and control guidance ^4,5. 2019-nCoV viral pneumonia is related to the seafood market when an unknown animal is responsible for the emergence of the outbreak ¹. Other countries started their surveillance borders to prevent the spread of the new unknown coronavirus especially when the Chinese new year holiday is in effect ⁶. Until 20 days ago, 41 cases are confirmed to be 2019-nCoV positives leaving one dead and seven in critical care. This number is grossly increasing every day and the number of confirmed cases at the date of writing this manuscript is more than 1400 and 80 deaths are confirmed in China (50 infections confirmed outside China) ⁷. The National Health Commission of China confirmed the human-to-human transmission of the Wuhan outbreak (2019-nCoV) five days ago ⁷. The symptoms include fever, malaise, dry cough, shortness of breath, and respiratory distress ¹.

2019-nCoV is a member of Betacoronaviruses family such as the Severe Acute Respiratory Syndrome Human coronavirus (SARS HCoV (8000 infections from which 774 dead)) and the Middle-East Respiratory Syndrome Human coronavirus (MERS HCoV (2500 infections from which 858 dead)) ^8,9. All the human coronaviruses (HCoVs) are zoonotic viruses that transmit from animals to humans through direct contact. Until today, seven different strains of Human coronaviruses (HCoVs) have been reported, including the newly emerged 2019-nCoV ^1,10. 229E and NL63 strains of HCoVs belong to Alphacoronaviruses while OC43, HKU1, SARS, MERS, and 2019-nCoV HCoVs belong to Betacoronaviruses ^1,8. SARS and MERS HCoV are the most aggressive strains of coronaviruses, leaving about 800 deaths each. SARS HCoV has a 10% mortality rate, while MERS HCoV has a 36% mortality rate, according to the WHO ^8,10-13. For the newly emerged coronavirus, the mortality rate is far lower (3%) than that of SARS and MERS but the fear is from its high transmission rate (human to human).

HCoVs generally are positive-sense single-stranded RNA (30kb) viruses. Two groups of protein characterize HCoVs; structural, such as Spike (S), Nucleocapsid (N) Matrix (M) and Envelope (E), and non-structural proteins such as RNA dependent RNA polymerase (RdRp) (nsp12) and the Papain-like protease PL^pro ⁸. PL^pro is an essential enzyme in the life cycle of RNA viruses, including coronaviruses. PL^pro is a multifunctional cysteine protease that processes the viral polyprotein and host cell proteins by hydrolysing the peptide and isopeptide bonds in viral and cellular substrates leading to the virus replication (Baez-Santos et al. 2014). PL^pro is targeted in different coronaviruses viruses, including SARS, MERS, and HCV ^14-18.

In this study, the 2019-nCoV PL^pro model is generated using homology modeling after sequence comparison to the solved structures in the protein data bank ¹⁹. Molecular docking is then performed to test some drugs (anti-SARS PL^pro and anti-HCV NS3) against 2019-nCoV PL^pro. The results suggest possible inhibition for the currently available therapeutics against the newly emerged coronavirus in silico.

Sequence alignment and modeling

The deposited gene for the newly emerged 2019-nCoV NC_045512.2 (last updated 17 January 2020) is retrieved from the National Center for Biotechnology Information (NCBI) nucleotide database then translated using ExPASy translate tool ²⁰ ²¹. Swiss Model is used to build a model for 2019-nCoV PL^pro ²². Using Basic Local Alignment Search Tool (BLAST) against the 2019-nCoV PL^pro we found eight different solved structures for SARS PL^pro (PDB IDs: 5TL6, 2FE8, 5E6J, 3MJ5, 5Y3E, 4M0W, 3E9S, and 4OVZ) that have at least 82.17% sequence identity to 2019-nCoV PL^pro²³. We choose the 5Y3E, chain A, because it is the best resolution (1.6 Å) structure among the eight SARS PL^pro. Therefore, 5Y3E is used as a template (82.8 % identity) for building 2019-nCoV PL^prousing the Swiss Model. Validation of the model is assessed by the Molprobity web server (Duke University), and the structure analysis and verification server (SAVES) (University of California Los Angles) ^24,25. PROCHECK ²⁶, Verify 3D ²⁷, PROVE ²⁸, and ERRAT ²⁹ in addition to the Ramachandran plot of the Molprobity are used to judge the validity of the model. Accordingly, the model is further energy minimized (MM3 force field), after the addition of missing Hydrogen atoms, by the computational chemistry workspace SCIGRESS to be ready for the docking experiments ^14,17,30-32.

Molecular Docking

Docking experiments are performed on the optimized 2019-nCoV PL^pro and the SARS PL^pro (PDB ID: 5Y3E, chain A) by the aid of AutoDock Vina software ³³. six different compounds (three anti-SARS and three anti-HCV) are tested against 2019-nCoV PL^pro. The anti-SARS compounds were N-(1,3-benzodioxol-5-ylmethyl)-1-[(1R)-1-naphthalen-1-ylethyl]piperidine-4-carboxamide (GRL-0667) ³⁴, 5-amino-2-methyl-N-[(1R)-1-naphthalen-1-ylethyl]benzamide (GRL-0617) ³⁵, and Mycophenolic acid ³⁶, while the anti-HCV drugs were the three approved (by FDA) drugs Telaprevir ³⁷, Boceprevir ³⁸, and Grazoprevir ³⁹.

After docking, the structures are analyzed through the Protein-Ligand Interaction Profiler (PLIP) web server (Technical University of Dresden) ⁴⁰.

2019-nCoV PL^promodeling

Figure 1A shows the pairwise sequence alignment of the PL^proof SARS and 2019-nCoV strains of coronavirus. SARS HCoV PL^prosecondary structure is presented at the top of the alignment (PDB ID: 5Y3E chain: A) while its water accessibility is presented at the bottom with blue indicating highly accessible residues, cyan partially accessible while white for the buried residues. Three black-dashed rectangles mark the active site residues (C112, H273, and D287) of both SARS HCoV and 2019-nCoV PL^pro. Figure 1B shows the pairwise sequence alignment of 2019-nCoV PL^proversus HCV NS3 (PDB ID: 3SU6). Orange-dashed rectangles surround the active site residues of HCV NS3 (H78, D102, and S159). As implied from the alignment, SARS PL^pro versus 2019-nCoV PL^pro shows high conservation (highlighted in red), called sequelogous. Despite the pairwise percent identity of 2019-nCoV PL^pro against SARS HCoV PL^pro is 82.8%, and only 11.85% for HCV NS3, the similarity to 2019-nCoV PL^pro is 93.81% and 59.68% for SARS PL^pro and HCV NS3, respectively. The active site triad C112, H273, and D287 of both SARS HCoV and 2019-nCoV PL^pro (figure 1A) are partially surface accessible in order for PL^pro to be able to attach its substrates for cleavage ⁴¹. For HCV NS3, the active site residues H78 and D102 are surface accessible as well (figure 1B) ⁴². This can be deduced from figure 1C, where the 2019-nCoV PL^pro model is represented by PyMOL software in the surface (right) and carton (left) representations. The three active site residues are in red (surface accessible) while the rest of the residues in green (see the enlarged panel). The surface accessibility is vital for the function of the protease, allowing the interaction with the substrates.

Figure 1 (A) Pairwise sequence alignment of SARS HCoV PLpro (PDB ID: 5Y3E) against the Wuhan 2019-nCoV PLpro. (B) Pairwise sequence alignment of HCV NS3 (PDB ID: 3SU6) against the Wuhan 2019-nCoV PLpro. Red highlights indicate identical residues, while yellow highlights are less conserved. Secondary structures are represented at the top of the alignments, while the surface accessibility is shown at the bottom (blue: highly accessible, cyan: partially accessible, while white is for buried). The black dashed rectangles mark active sites of both 2019-nCoV PLpro and SARS PLpro (C112, H273, and D287) while orange rectangles mark the active site of HCV NS3 (H78, D102, and S159). The alignment is performed using the CLUSTAL omega web server and represented by ESpript 3. (C) The newly emerged Wuhan 2019-nCoV PLpro model built by Swiss Model in the green cartoon (left) and surface (right) representations. The active site residues are represented in red sticks for clarification (see the enlarged panel).

The complete genome for 2019-nCoV has a BLAST sequence identity of 89.12 % and 82.34% with Bat SARS-like coronavirus isolate bat-SL-CoVZC45 and SARS coronavirus ZS-C, respectively. Drug designers should take care of the identity, especially when emerging RNA viruses that have a high mutation rate are targeted. On the other hand, potent drugs could undetectably present on shelves able to stop the rapidly emerging 2019-nCoV strain.

2019-nCoV PL^pro model (315 residues) is built by the aid of the Swiss Model using SARS HCoV PL^pro (PDB ID: 5Y3E, chain A) as a homolog. The model is sequelogous (82.8% id) to the template suggesting a high-quality model obtained. The model is valid based on the values of the Ramachandran plot (100% in the allowed region and 92.9% in the most favored region). Besides, 92.04% of the residues have averaged a 3D-1D score of ≤ 0.2 (Verify 3D software), while the overall quality factor (ERRAT software) is 94.8%. PROVE software gives 2.7% atomic volumes outliers, which is acceptable.

Figure 2 2D structures of the anti-SARS PLpro drugs (top) (GRL-0667, GRL-0617, and Mycophenolic acid) and anti-HCV NS3 drugs (bottom) (Telaprevir, Boceprevir, and Grazoprevir) retrieved from PubChem database. Carbon atoms not explicitly represented by a letter, but with black lines, N stands for Nitrogen, O stands for Oxygen, S stands for Sulfur, and H stands for Hydrogen.

Anti-SARS and anti-HCV binding to 2019-nCoV PL^pro

Before performing the docking experiments, the structures of the small molecules, the 2019-nCoV PL^pro model and SARS PL^pro structure (PDB ID: 5Y3Q, Chain A), are prepared. The missing Hydrogen atoms are added to the protein structure and model, while any water molecules or ligands are removed from the SASR structure. Ligand structures are retrieved from the protein data bank files to be in the optimized active form. Figure 2 shows the 2D structures of the anti-SARS PL^pro (top) and anti-HCV NS3 (bottom) drugs. The anti-SARS PL^pro GRL-0667, GRL-0617, and mycophenolic acids are retrieved from the PDB files 3MJ5 (GRM), 3E9S (TTT), and 1JR1 (MOA), respectively. Besides, the anti-HCV NS3 Telaprevir, Boceprevir, and Grazoprevir are retrieved from the PDB files 3SV6 (SV6), 3LOX (MCX), and 3SUD (SUE), respectively.

The active site of the proteins (2019-nCoV PL^pro and SARS PL^pro) is treated as flexible during the docking experiments. A grid box of size 30 Å × 36 Å × 30 Å centered at (-17.9, 43.9, 1.6) Å is prepared for 2019-nCoV PL^pro utilizing the AutoDock tools ⁴³. Additionally, a grid box of size 30 Å × 34 Å × 30 Å centered at (-75.6, -3.8, 109.8) Å is prepared for SARS PL^pro. AutoDock Vina is used to predicting the interaction between the anti-SARS and anti-HCV proteases drugs against the active site of 2019-nCoV PL^pro. Figure 3 shows the docking score values for 2019-nCoV PL^pro (blue line), SARS HCoV PL^pro (orange line), and HCV NS3 (gray line).

Figure 3 Binding energies calculated by AutoDock Vina for the docking of the anti-SARS PLpro drugs (GRL-0667, GRL-0617, and Mycophenolic acid) and anti-HCV NS3 drugs (Telaprevir, Boceprevir, and Grazoprevir) against 2019-nCoV PLpro (blue line), SARS PLpro (orange line), and HCV NS3 (gray line).

As reflected from the docking scores, the six compounds can bind to 2019-nCoV PL^pro, SARS HCoV PL^pro, and HCV NS3 with good binding energy (-5.7 up to -11.0 kcal/mol). There is a reduction in the binding energies for the drugs to 2019-nCoV PL^pro compared to other proteases. For GRL-0667, GRL-0617, and Mycophenolic acid, the reduction in the binding energies for 2019-nCoV PL^pro is 25%, 21%, and 30%, respectively compared to SARS PL^pro. While, in the case of HCV, the reduction in the 2019-nCoV PL^pro binding energies is 18%, 11%, and 38% for Telaprevir, Boceprevir, and Grazoprevir, respectively. Despite this reduction, the PL^proof 2019-nCoV still able to bind the drugs with good binding energies (-5.7 up to -7 kcal/mol), which is enough to maintain the viral protein dysfunctionally.

To further analyze the binding patterns, we examined the interaction complexes formed upon docking by the aid of the PLIP web server. Figures 4A and 4B show the interactions that formed after docking of the anti-SARS (GRL-0667, GRL-0617, and Mycophenolic acid) and anti-HCV drugs (Telaprevir, Boceprevir, and Grazoprevir), respectively. The solid blue lines indicate H-bonding, while dashed grey lines indicate hydrophobic interactions. The salt bridges and the π-π contacts are represented in balls connected by yellow dashed lines, and green dashed lines, respectively. The labeled residues (blue sticks) represent the 2019-nCoV active residues that interact with the ligands (orange sticks). Tables 1 and 2 show the interaction pattern that established upon docking for the anti-SARS drugs and the anti-HCV drugs, respectively. The binding energies are listed in the table along with the number of formed H-bonds and the number of hydrophobic interactions established after docking. The amino acids from the 2019-nCoV PL^pro that engaged in the interaction with the ligands are listed as well in tables 1 and 2.

Figure 4 The interaction pattern for 2019-nCoV PLpro against the anti-SARS PLpro (A) and anti-HCV NS3 (B). PyMOL software is used to represent the docking poses using colored sticks. Orange sticks represent the drugs while blue stick for the 2019-nCoV PLpro residues involved in the binding (labeled with its three-letter codes). Blue solid lines represent H-bonds while hydrophobic interactions are grey-dashed lines. Salt bridges and π-π contacts are in dashed lines between two yellow spheres and green-dashed lines, respectively.

Additionally, the results of the interactions of SARS PL^pro against anti-SARS drugs are listed in table 1, while the anti-HCV drugs’ interactions with HCV NS3 are listed in table 2 for comparison. The most-reported residues from the 2019-nCoV PL^pro that take part in the interaction through H-bonding or hydrophobic interactions are K105 and W106 (bold residues in tables 1 and 2). As implies from the tables, both SARS PL^pro and HCV NS3 have a higher number of interactions established upon docking the tested drugs compared to the new coronavirus strain. However, there are a minimum number of established interactions (seven interactions) that stabilize the drugs in the protein active site for 2019-nCoV PL^pro. Besides, in all docking experiments, the established interactions are both H-bonding and hydrophobic interactions in addition to few salt bridges (stared residues in the tables 1 and 2) suggesting the possibility of these drugs (anti-SARS and anti-HCV drugs) to bind to and inhibit the function of the crucial viral enzyme PL^pro.

Table 1 The interactions formed between anti-SARS compounds (GRL-0667, GRL-0617, and Mycophenolic acid) and 2019-nCoV PL^pro upon docking. The Star (*) represents salt bridges while the douple stars (**) represents π-π contact.

		*Docking score (kcal/mol)*	*H-bonding*		*Hydrophobic interaction*
Anti-SARS		*Docking score (kcal/mol)*	number	Residues involved	number	Residues involved
GRL-0667	2019-nCoV	-7.0	3	W93, K105, W106	7	K92, W106 (2), W106(3)**, A107
GRL-0667	SARS	-9.3	6	W107, C112, G164, D165*, G272, Y274	5	Y113, L163, Y265, Y274 (2)

GRL-0617	2019-nCoV	-6.6	2	L162, Y264	8	L162, P247, P248, Y264 (2), Y268 (2), T301
GRL-0617	SARS	-8.4	4	L163, D165 (2), Y274	5	D165, P249, Y265, Y269, T302

Mycophenolic Acid	2019-nCoV	-5.7	7	K105, W106 (2), H272, H272, D286, A288	1	L289
Mycophenolic Acid	SARS	-8.2	3	G164, G272, Y274	1	Y265

Table 2 The interactions formed between anti-HCV compounds (Telaprevir, Boceprevir, and Grazoprevir) and 2019-nCoV PLpro upon docking. The Star (*) represents salt bridges while the douple stars (**) represents π-π contact.

		*Docking score (kcal/mol)*	*H-bonding*		*Hydrophobic interaction*
Anti-HCV		*Docking score (kcal/mol)*	number	Residues involved	number	Residues involved
Telaprevir	2019-nCoV	-6.6	8	W106, T265, H272, K274, D286 (3), A288	3	K105, W106 (2)
Telaprevir	HCV	-8.0	10	Q59 (3), H75, K154, G155, S157 (2), A175 (2)	6	I150, L153, K154, F172, A174 (2)

Boceprevir	2019-nCoV	-6.6	4	W106, N109 (2), H272	5	K105, W106 (4)
Boceprevir	HCV	-7.4	10	H75 (2), G155, S157 (3) ,R173, A175 (3)	7	H75 (2), I150, K154 (2), V176, D186

Grazoprevir	2019-nCoV	-6.8	4	K105, W106, K274, D286	3	W106, T265, L289
Grazoprevir	HCV	-11.0	10	H75 (2), G155, S156, S157 (3), R173, A175 (2)	13	Q59, F61 (2), H75 (2), H75**, D99, I150, F172, R173, a175, V176, D186

In summary, both anti-SARS PL^pro (GRL-0667, GRL-0617, and Mycophenolic acid) and anti-HCV NS3 (Telaprevir, Boceprevir, and Grazoprevir) can bind to the active site (C112, H273, and D287) of 2019-nCoV PL^pro. The binding energies for 2019-nCoV PL^pro are slightly less than that calculated for SARS PL^pro and HCV. On the other hand, at least seven interactions are established between 2019-nCoV PL^pro and each tested compound in this study (either H-bonds or hydrophobic interactions) suggesting possible targeting of 2019-nCoV PL^pro using anti-SARS and anti-HCV drugs.

Wuhan's novel coronavirus has a significant health concern since the last outbreak of these types of viruses. SARS in the year 2002 to 2003 in China left more than 700 deaths and 8000 cases in hospitals. Middle East region has an entirely different infection pattern of MERS leaving again about 800 deaths and 2500 hospitalizations. The present study aimed to test and suggest possible inhibitor drugs used against SARS and HCV proteases. Both anti-SARS PL^pro (GRL-0667, GRL-0617, and Mycophenolic acid) and anti-HCV NS3 (Telaprevir, Boceprevir, and Grazoprevir) can bind to the active site of 2019-nCoV PL^pro and hence, may contradict viral replication.

Competing Interest

All the authors declare that there is no competing interest in this work.

Data Availability

The docking structures are available upon request from the corresponding author

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Anti-SARS and anti-HCV drugs repurposing against the Papain-like protease of the newly emerged coronavirus (2019-nCoV)

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