Use of coronavirus SL5s as targets in preparation of drug for preventing and treating coronavirus infection

Abstract

Disclosed is use of coronavirus SL5s as targets in the preparation of a drug for preventing and treating coronavirus infection. The drug target coronavirus SL5s described in the present invention are the stem-loops 5 of the 5'UTR regions of coronaviruses, which participate in regulating viral mRNA translation. Further disclosed is an inhibitor of the SL5s of 7 human infectious coronaviruses, i.e., an antisense oligonucleotide specifically targeting the SL5s for inhibiting coronavirus infection. Experiments have demonstrated that the application of the antisense oligonucleotide specifically targeting the coronavirus SL5s in vitro can significantly inhibit the translation levels of the coronavirus mRNAs. The coronavirus SL5s described in the present invention can be used as drug targets to screen for candidate drugs for inhibiting coronavirus mRNA translation, showing great significance for the development of anti-coronavirus drugs and the prevention and treatment of coronaviruses in the future.

Description

Application of coronavirus SL5 as a target in preparation of a drug for preventing and treating coronavirus infection TECHNICAL FIELD

[0001] The present application relates to the field of biomedical technology, in particular to the application of coronavirus SL5 as a target in preparation of a drug for preventing, alleviating and / or treating coronavirus infection or a disease caused by coronavirus infection. BACKGROUND

[0002] Coronaviruses are prone to gene recombination and mutation during evolution, resulting in genetic diversity and a wide range of hosts, which provides conditions for coronavirus cross-species transmission. Currently, seven coronaviruses that can infect humans have been found, including four human coronaviruses HCoV-OC43, HCoV-HKU1, HCoV-NL63 and HCoV-229E that cause mild respiratory diseases, and three highly pathogenic coronaviruses SARS-CoV, MERS-CoV and SARS-CoV-2 that cause pandemics. The approved anti-SARS-CoV-2 drugs are mostly small molecule drugs targeting viral proteins. However, within the Coronaviridae family, different coronaviruses belong to different genera, and their protein sequences differ greatly. Even the same virus, such as SARS-CoV-2, will develop drug resistance due to the high mutation rate of the viral protein coding gene. Therefore, the existing antiviral drugs lack broad-spectrum and cannot cope with multiple coronaviruses and potential coronaviruses with cross-species transmission risk in the future, and there is an urgent need to explore new broad-spectrum drug targets.

[0003] Small molecule drugs against SARS-CoV-2 mainly target viral polymerase, and such drugs can inhibit the replication process of viral genome. However, during the process of viral mutation, mutations in viral polymerase continue to accumulate, and therefore, viral polymerase inhibitors are prone to drug resistance. For example, baloxavir inhibits viral replication by inhibiting the endonuclease activity of the PA protein in viral polymerase to block the synthesis of viral mRNA. However, a phase III clinical trial conducted in Japan in 2018 found that 9.7% of patients developed drug-resistant mutant virus strains after receiving baloxavir treatment, indicating that the drug development strategy targeting viral polymerase is prone to drug resistance and difficult to achieve broad-spectrum antiviral effect. In addition to targeting viral replication polymerase, the viral genome as a template for viral replication also has the potential to become a drug target. The coronavirus genome includes coding and non-coding regions. By comparing the sequences of various coronavirus genomes, it is found that the homology of the coding region is 54.2%, while the homology of the non-coding region is as high as 83.6%, revealing the high conservation of the non-coding region among different coronaviruses. The coronavirus non-coding region is located at the beginning and end of the viral genome and is a key nucleic acid region essential for viral replication and transcription. Therefore, an antiviral drug designed by targeting the highly conserved non-coding region can achieve broad-spectrum antiviral effect and overcome the problem of drug resistance. Currently, there is no broad-spectrum antiviral drug designed to target the coronavirus non-coding region, and there is an urgent need in the field to discover a new broad-spectrum drug target targeting the coronavirus non-coding region for the development of antiviral drugs to prevent and treat various coronavirus infections. SUMMARY

[0004] OBJECTIVE

[0005] The purpose of the present application is to provide a strategy that can be used for the treatment of coronavirus infection or diseases caused by coronavirus infection, i.e., targeting the stem-loop structure SL5 in the non-coding region of the coronavirus genome to prepare drugs for preventing and treating coronavirus infection and the application thereof.

[0006] SOLUTION

[0007] To achieve the objective of the present application, the present application provides the following technical solutions:

[0008] The present application provides the use of coronavirus SL5 as a target in the preparation of drugs for preventing, alleviating and / or treating coronavirus infection or diseases caused by coronavirus infection.

[0009] The coronavirus SL5 includes but is not limited to at least one of the following coronavirus SL5:

[0010] The novel coronavirus SARS-CoV-2 SL5 has a nucleotide sequence as shown in SEQ ID NO: 1:

[0011] Atypical coronavirus SARS-CoV SL5, the nucleotide sequence of which is shown as SEQ ID NO: 2:

[0012] Middle East respiratory syndrome coronavirus MERS-CoV SL5, the nucleotide sequence of which is shown as SEQ ID NO: 3:

[0013] Human coronavirus OC43 HCoV-OC43 SL5, the nucleotide sequence of which is shown as SEQ ID NO: 4:

[0014] Human coronavirus HKU1 HCoV-HKU1 SL5, the nucleotide sequence of which is shown as SEQ ID NO: 5:

[0015] Human coronavirus NL63 HCoV-NL63 SL5, the nucleotide sequence of which is shown as SEQ ID NO: 6:

[0016] Human coronavirus 229E HCoV-229E SL5, the nucleotide sequence of which is shown as SEQ ID NO: 7:

[0017] Further, the nucleotide sequence of the coronavirus SL5 has at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or more sequence identity to SEQ ID NO: 1-7.

[0018] Further, the coronavirus can also be a coronavirus that infects mammals and birds, and the nucleotide sequence of the coronavirus SL5 is shown in the above-mentioned nucleotide sequence of the coronavirus SL5 that can infect humans.

[0019] The diseases caused by the coronavirus infection include COVID-19, Severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and upper respiratory disease.

[0020] This invention also provides the use of coronavirus SL5 inhibitors in the preparation of medicaments for the prevention, mitigation and / or treatment of coronavirus infection or diseases caused by coronavirus infection.

[0021] The coronavirus SL5 inhibitor includes any of the following:

[0022] A1) Substances that inhibit the replication, transcription, and / or post-transcriptional modification of the target;

[0023] A2) Substances that reduce the expression, activity, and / or function of the target;

[0024] The targets include, but are not limited to, SARS-CoV-2SL5, SARS-CoV SL5, MERS-CoV SL5, HCoV-OC43 SL5, HCoV-HKU1 SL5, HCoV-NL63 SL5 and / or HCoV-229E SL5.

[0025] The coronavirus SL5 inhibitors include substances that cause the target to be missing or have its expression reduced through knockdown, editing, and / or knockout techniques, or substances that target the target to reduce its content or inactivate its function.

[0026] Preferably, the use of knockdown techniques (including RNA interference, Morpholino interference, antisense nucleic acid technology, and ribozyme technology), editing techniques (including zinc finger ribozyme knockout, TALEN editing, and CRISPR editing), or knockout techniques (including complete knockout and conditional knockout) to inhibit, silence, or eliminate expression is well known to those skilled in the art. For example, expression can be inactivated or silenced at the post-transcriptional level using shRNA, siRNA, or miRNA targeting the target. Alternatively, a CRISPR-Cas system containing sgRNA and Cas protein can be used to knock out the target.

[0027] The coronavirus SL5 inhibitor is an antisense oligonucleotide, locked nucleic acid, siRNA, shRNA, sgRNA, or small molecule inhibitor that specifically targets coronavirus SL5.

[0028] The antisense oligonucleotide that specifically targets coronavirus SL5 includes at least one of the following antisense oligonucleotides:

[0029] The antisense oligonucleotide sequence that specifically targets SARS-CoV-2SL5 is (SEQ ID NO:8);

[0030] The antisense oligonucleotide sequence that specifically targets SARS-CoV SL5 is (SEQ ID NO:9);

[0031] The antisense oligonucleotide sequence that specifically targets MERS-CoV SL5 is (SEQ ID NO:10);

[0032] The antisense oligonucleotide sequence that specifically targets HCoV-OC43 SL5 is (SEQ ID NO:11);

[0033] The antisense oligonucleotide sequence that specifically targets HCoV-HKU1 SL5 is (SEQ ID NO:12);

[0034] The antisense oligonucleotide sequence that specifically targets HCoV-NL63 SL5 is (SEQ ID NO:13);

[0035] The antisense oligonucleotide sequence that specifically targets HCoV-229E SL5 is (SEQ ID NO:14).

[0036] The diseases caused by the coronavirus infection include COVID-19, Severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and upper respiratory disease.

[0037] The present invention also provides a drug / drug composition for the treatment of coronaviruses, said drug / drug composition comprising an effective amount of a pharmacologically acceptable coronavirus SL5 inhibitor as described above;

[0038] And pharmaceutically acceptable carriers.

[0039] The coronavirus SL5 inhibitor is capable of inhibiting coronavirus SL5 expression and / or function.

[0040] The present invention also provides the use of the said drug / drug composition in the preparation of a medicament for the prevention, relief and / or treatment of coronavirus infection or disease caused by coronavirus infection.

[0041] The diseases caused by the coronavirus infection include COVID-19, Severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and upper respiratory disease.

[0042] The present invention also provides a coronavirus detection reagent / kit, the reagent / kit comprising: coronavirus SL5 as described above, or coronavirus SL5 inhibitor as described above, or drug / drug composition as described above.

[0043] The present invention also provides the application of the aforementioned detection reagent / kit in the non-diagnostic detection of coronaviruses.

[0044] The diseases caused by the coronavirus infection include COVID-19, Severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and upper respiratory disease.

[0045] The present invention also provides a method for screening drugs to prevent, alleviate and / or treat coronavirus infection or diseases caused by coronavirus infection, the method comprising: targeting coronavirus SL5 as a drug target, and searching for substances that can inhibit the expression and / or function of coronavirus SL5 as candidate drugs.

[0046] Preferably, the method includes: applying a candidate drug to cells in vitro, and then detecting the luciferase activity in the viral translation reporter system of the cells after culturing.

[0047] Researchers can determine whether a drug is therapeutically significant by detecting the activity of coronavirus SL5-mediated luciferase in cells after drug application. Generally, drugs that inhibit coronavirus SL5-mediated viral mRNA translation by more than 50% compared to the control group can be considered therapeutically significant.

[0048] The diseases caused by the coronavirus infection include COVID-19, Severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and upper respiratory disease.

[0049] The present invention further provides a method for preventing, alleviating, and / or treating coronavirus infection or disease caused by coronavirus infection, comprising administering an effective amount of the coronavirus SL5 inhibitor as described above to a subject in need (such as a mammal). The method may also be in vitro or non-therapeutic.

[0050] The subjects may be patients infected with coronavirus or individuals seeking to prevent coronavirus infection. The coronavirus SL5 inhibitor or drug may be administered to the subjects before, during, or after receiving anti-coronavirus treatment.

[0051] In this invention, the diseases caused by coronavirus infection include COVID-19, Severe acute respiratory syndrome (SARS), and Middle East respiratory syndrome (MERS). Beneficial effects

[0052] This invention is the first to propose the function and role of coronavirus SL5, providing a drug target for the prevention, mitigation, and / or treatment of coronavirus infection or disease caused by coronavirus infection. This invention has the following advantages:

[0053] (1) This invention proposes that coronavirus SL5 is crucial for viral infection, and therefore coronavirus SL5 can be used as a drug target to prepare drugs for the prevention and treatment of coronavirus infection;

[0054] (2) The present invention applies antisense oligonucleotides that specifically target coronavirus SL5 in vitro, and proposes that the translation level of coronavirus mRNA in cells is significantly inhibited after drug application;

[0055] (3) This invention provides a method for screening drugs for the prevention, relief and / or treatment of coronavirus infection or diseases caused by coronavirus infection by detecting the level of coronavirus mRNA translation in cells after the application of coronavirus SL5 inhibitor.

[0056] In view of the above, the coronavirus SL5 described in this invention has the function of regulating viral infection and can be used as a drug target, which is of great significance for the future development of anti-coronavirus drugs and prevention and treatment. Attached Figure Description

[0057] To more clearly illustrate the technical solutions in the embodiments of the present invention, the accompanying drawings used in the description of the embodiments will be briefly introduced below. Obviously, the accompanying drawings described below are some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0058] Figure 1 shows the functional verification of the coronavirus SL5;

[0059] Figure 2 shows the ASO design for the coronavirus SL5;

[0060] Figure 3 shows the ASO inhibition effect of seven coronaviruses. Detailed Implementation

[0061] The present invention will now be described in detail with reference to specific embodiments and accompanying drawings, thereby making the advantages and various effects of the present invention more clearly apparent. Those skilled in the art should understand that these specific embodiments and examples are for illustrative purposes only and are not intended to limit the present invention.

[0062] Throughout this specification, unless otherwise specified, the terminology used in this invention should be understood as having the meaning commonly used in the art. Therefore, unless otherwise defined, all technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. In the event of any conflict, this specification shall prevail.

[0063] Unless otherwise specified, all raw materials, reagents, instruments and equipment used in this invention can be obtained by purchasing them from the market or by existing methods.

[0064] The technical solution of this invention is to solve the above-mentioned technical problems, and the overall idea is as follows:

[0065] Coronaviruses are single-stranded positive-sense RNA viruses. After entering a host cell, the viral genome can act as mRNA, directing viral protein synthesis via host ribosomes. The 5' untranslated region (UTR) of coronaviruses is a crucial element regulating viral mRNA translation, modulating translational activity, half-life, and protein expression levels through interactions with RNA-binding proteins. Therefore, elucidating the function of the coronavirus 5'UTR helps us understand the pathogenic mechanism of coronaviruses, providing a scientific basis and practical application value for the development of live attenuated vaccines. This invention investigates the function of SL5 in seven human-infecting coronaviruses. The coronavirus 5'UTR can form multiple stem-loop structures, with the fifth stem-loop structure, SL5, being a key stem-loop mediating coronavirus translation. The coronavirus SL5 inhibitor described in this invention can significantly inhibit coronavirus mRNA translation, providing new ideas and solutions for the development of anti-coronavirus drugs. Specifically:

[0066] This invention first predicted the interaction region between the coronavirus 5'UTR and the coronavirus translation regulatory protein NSP1 using a bioinformatics website, discovering that stem-loop SL5 in the coronavirus 5'UTR plays a crucial role. Furthermore, using TargetFinfer and PFRED software, antisense oligonucleotide molecules (with nucleotide sequences as shown in SEQ ID NO:8-14) targeting coronavirus SL5 were designed as coronavirus SL5 inhibitors. These coronaviruses include seven viruses: SARS-CoV-2, SARS-CoV, MERS-CoV, HCoV-OC43, HCoV-HKU1, HCoV-NL63, and HCoV-229E. This invention utilized a coronavirus mRNA translation reporter system to find that the aforementioned antisense oligonucleotide molecules significantly inhibited viral mRNA translation levels. Therefore, the coronavirus SL5 described in this invention can serve as a target for screening drugs that inhibit coronavirus infection, showing promising application prospects.

[0067] The following will provide a detailed description of the application of the proposed coronavirus SL5 as a drug target for the prevention and treatment of coronavirus infection, in conjunction with examples and experimental data.

[0068] Example 1: Design of antisense oligonucleotide drugs targeting coronavirus SL5

[0069] 1. Coronavirus 5'UTR Functional Region Filtering

[0070] RNA regions with complex secondary structures tend to bind tightly to proteins. This invention, through secondary structure analysis of the SARS-CoV-2 5'UTR, found that SL5 is the longest and most structurally complete stem-loop in the 5'UTR region, indicating that SL5 may play a crucial role in the translational regulation function of the 5'UTR. This invention used the catRAPID website to predict the interaction regions between the 5'UTR and the viral translation regulatory protein NSP1. As shown in Figure 1, the 5'UTR consists of six stem-loop structures: SL1, SL2, SL3, SL4, SL4.5, and SL5. The prediction results show that the SL5 stem-loop in the SARS-CoV-2 5'UTR has the strongest binding affinity to the viral translation regulatory protein NSP1, indicating that SL5 plays the most important role in viral genome translation. This invention, through viral secondary structure comparison, found that the SL5 stem-loop is highly conserved in seven coronaviruses that can infect humans. Therefore, this invention further speculates that SL5 is also a key stem-loop in the interaction between the 5'UTR and NSP1 of the other six coronaviruses, and can regulate the translation of coronavirus mRNA.

[0071] 2. ASO drug design targeting coronavirus SL5

[0072] This invention downloaded the genome sequences of seven human-infecting coronaviruses from NCBI and performed secondary structure analysis on the 5'UTR sequences of the seven coronaviruses using RNAFolding software. The invention extracted the nucleotide sequence of coronavirus SL5 and used TargetFinder software to test the feasibility of SL5 as a target for antisense oligonucleotide (ASO) drugs. The results showed that the second stem-loop of SL5 had high scores. Furthermore, this invention designed seven ASO drugs specifically targeting coronavirus SL5 using PFRED software, as shown in Figure 2.

[0073] Based on the above ASO drug design, Genscript Biotech Inc. synthesized the corresponding ASO drugs, and the ASO drug sequences are shown in Table 1:

[0074] Table 1 - ASO Drug Sequence

[0075] Example 2: Functional validation of antisense oligonucleotide drugs targeting coronavirus SL5

[0076] 1. Establish a reporting system for weakened 5'UTR function of the coronavirus.

[0077] To investigate the ASO function of coronavirus SL5, this invention inserts the coronavirus 5'UTR as an mRNA translation regulatory element between the CMV promoter and the luciferase reporter, constructing a full-length 5'UTR reporter system, where the luciferase expression level represents the viral mRNA translation level. Primers for 5'UTR amplification of different coronaviruses are shown in Table 2.

[0078] Table 2 - Primer Sequences

[0079] 2. Validate the ASO function of drugs targeting coronavirus SL5

[0080] To verify the efficacy of ASO drugs targeting coronavirus SL5, this invention utilizes the coronavirus 5'UTR translation report system to verify whether viral mRNA translation levels are inhibited after ASO drug treatment.

[0081] This invention investigated the effects of different ASO drugs on viral mRNA translation levels in 293T cells. First, 293T cells were seeded in 24-well plates, and transfection began when the cell density reached 60-70%. The ASO drug was diluted to 10 μM, and each group was co-transfected with 500 ng of the coronavirus 5'UTR translation reporter system plasmid, 100 ng of the viral translation regulatory protein expression plasmid, and 50 nM of the ASO drug targeting SL5. The transfected cells were cultured at 37°C for 24 h, and luciferase activity was detected after cell lysis. The experimental results are shown in Figure 3. Compared with the control group, the viral mRNA translation levels of all seven coronaviruses were significantly reduced after transfection with the ASO drug, indicating that the ASO drug specifically targeting coronavirus SL5 can inhibit viral translation and thus exert an antiviral effect. Therefore, coronavirus SL5 can serve as a drug target for anti-coronavirus infection, providing a novel target and design strategy for anti-coronavirus drug development.

[0082] Finally, it should be noted that the terms “comprising,” “including,” or any other variation thereof are intended to cover non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements includes not only those elements but also other elements not expressly listed, or elements inherent to such process, method, article, or apparatus.

[0083] Although preferred embodiments of the invention have been described, those skilled in the art, upon learning the basic inventive concept, can make other changes and modifications to these embodiments. Therefore, the appended claims are intended to be interpreted as including the preferred embodiments as well as all changes and modifications falling within the scope of the invention.

[0084] Obviously, those skilled in the art can make various modifications and variations to this invention without departing from its spirit and scope. Therefore, if these modifications and variations fall within the scope of the claims of this invention and their equivalents, this invention also intends to include these modifications and variations.

Claims

1. Use of coronavirus SL5 as a target in the preparation of a medicament for preventing, alleviating and / or treating coronavirus infection or a disease caused by coronavirus infection.

2. Use according to claim 1, wherein The coronavirus SL5 includes at least one of the following: SARS-CoV-2 SL5, the nucleotide sequence of which is shown as SEQ ID NO: 1; SARS-CoV SL5, the nucleotide sequence of which is shown as SEQ ID NO: 2; MERS-CoV SL5, the nucleotide sequence of which is shown as SEQ ID NO: 3; HCoV-OC43 SL5, the nucleotide sequence of which is shown as SEQ ID NO: 4; HCoV-HKU1 SL5, the nucleotide sequence of which is shown as SEQ ID NO: 5; HCoV-NL63 SL5, the nucleotide sequence of which is shown as SEQ ID NO: 6; HCoV-229E SL5, the nucleotide sequence of which is shown as SEQ ID NO:

7.

3. Use of a coronavirus SL5 inhibitor in the preparation of a medicament for preventing, alleviating and / or treating coronavirus infection or a disease caused by coronavirus infection.

4. Use according to claim 3, wherein the compound is ###0002### The coronavirus SL5 inhibitor includes any of the following: A1) a substance that inhibits the replication, transcription and / or post-transcriptional modification of the target; A2) a substance that reduces the expression, activity and / or function of the target; The target includes SARS-CoV-2 SL5, SARS-CoV SL5, MERS-CoV SL5, HCoV-OC43 SL5, HCoV-HKU1 SL5, HCoV-NL63 SL5 and / or HCoV-229E SL5.

5. The use according to claim 4, wherein the compound is ###0002### The coronavirus SL5 inhibitor includes an antisense oligonucleotide, a locked nucleic acid, an siRNA, an shRNA, an sgRNA or a small molecule inhibitor that specifically targets coronavirus SL5.

6. The use according to claim 5, wherein the compound is ###0002### The antisense oligonucleotide that specifically targets coronavirus SL5 includes at least one of the following antisense oligonucleotides: The antisense oligonucleotide sequence that specifically targets SARS-CoV-2 SL5 is shown as SEQ ID NO: 8; The antisense oligonucleotide sequence that specifically targets SARS-CoV SL5 is shown as SEQ ID NO: 9; The antisense oligonucleotide sequence that specifically targets MERS-CoV SL5 is shown as SEQ ID NO: 10; The antisense oligonucleotide sequence that specifically targets HCoV-OC43 SL5 is shown as SEQ ID NO: 11; The antisense oligonucleotide sequence that specifically targets HCoV-HKU1 SL5 is shown as SEQ ID NO: 12; The antisense oligonucleotide sequence that specifically targets HCoV-NL63 SL5 is shown as SEQ ID NO: 13; The antisense oligonucleotide sequence that specifically targets HCoV-229E SL5 is shown as SEQ ID NO:

14. The antisense oligonucleotide sequence specifically targeting HCoV-229E SL5 is shown as SEQ ID NO:

14.

7. A pharmaceutical / drug composition for use against coronavirus, characterized by, The drug / drug composition comprises: an effective amount of a pharmacologically acceptable coronavirus SL5 inhibitor as described in any one of claims 3-6; and a pharmaceutically acceptable carrier.

8. A coronavirus detection reagent / kit, characterized by, The reagent / kit comprises: the coronavirus SL5 as described in claim 1 or 2, or the coronavirus SL5 inhibitor as described in any one of claims 3-6, or the drug / drug composition as described in claim 7.

9. Use of the anti-coronavirus drug / drug composition of claim 7 in the preparation of a drug for preventing, alleviating and / or treating a coronavirus infection or a disease caused by a coronavirus infection, or use of the coronavirus detection reagent / kit of claim 8 in the detection of a coronavirus for non-diagnostic purposes.

10. A method of screening for a drug for preventing, alleviating and / or treating a coronavirus infection or a disease caused by a coronavirus infection, characterized by, The method comprises: taking the coronavirus SL5 as described in claim 1 as a drug target, and searching for a substance capable of inhibiting the expression and / or function of the coronavirus SL5 as a candidate drug.

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