Ursodeoxycholic acid may protect from severe acute respiratory syndrome coronavirus 2 Omicron variant by reducing angiotensin‐converting enzyme 2
Kyungmin Lee, Yujeong Na, Minjin Kim, Dongjin Lee, Jongseo Choi, Gwanyoung Kim, Min‐soo Kim
Pharmacology Research & Perspectives, doi:10.1002/prp2.1194
The SARS-CoV-2 caused COVID-19 pandemic has posed a global health hazard. While some vaccines have been developed, protection against viral infection is not perfect because of the urgent approval process and the emergence of mutant SARS-CoV-2 variants. Here, we employed UDCA as an FXR antagonist to regulate ACE2 expression, which is one of the key pathways activated by SARS-CoV-2 Delta variant infection. UDCA is a well-known reagent of liver health supplements and the only clinically approved bile acid. In this paper, we investigated the protective efficacy of UDCA on Omicron variation, since it has previously been verified for protection against Delta variant. When co-housing with an Omicron variant-infected hamster group resulted in spontaneous airborne transmission, the UDCA pre-supplied group was protected from weight loss relative to the non-treated group at 4 days post-infection by more than 5%-10%. Furthermore, UDCA-treated groups had a 3-fold decrease in ACE2 expression in nasal cavities, as well as reduced viral expressing genes in the respiratory tract. Here, the data show that the UDCA serves an alternative option for preventive drug, providing SARS-CoV-2 protection against not only Delta but also Omicron variant. Our results of this study will help to propose drug-repositioning of UDCA from liver health supplement to preventive drug of SARS-CoV-2 infection.
compared to the mock group (Figure 3B ; Figure S2C ). Since ACE2 functions as a receptor, interactions with viruses or other stimuli may alter the ACE2 expression by ACE2 shedding or ACE2-expressing cell death during Omicron infection. 36 Besides, in Syrian hamsters, ACE2 expression is relatively low in the lung samples. 37 Confirming the reduction in expression brought on by UDCA may be challenging given the low level of ACE2 expression in the lungs of Syrian hamsters. We found that UDCA treatment lowered lung damage caused by viral infection on 4 dpi (Figure S1 ). Directly infected hamsters showed a relatively higher inflammation score of 2.00 ± 0.41 points at 2 dpi and 1.75 ± 1.19 points at 4 dpi. In the mock group, the score was similarly boosted to 0.67 ± 0.58 points on 4 dpi within the histological investigation on the lung lesions. At both time points, there were no pathological changes in UDCA and Molnupiravir groups. Similarly, whereas no plaque was found in UDCA-treated group, the mock group had significant viral replication on 4 dpi (Figure S3C ). The donor group had the highest viral RNA level and titer at 2 dpi, while the mock group had the highest at 4 dpi. Since 5 or 7 days after infection, the viral load may have been lowered by spontaneous recovery in the donor group. In contrast, viral replication might be started in the early stages of infection by airborne transmission in the mock group. Viral replication of the Omicron variant is higher in the..
References
Abadi, Jeshvaghani, Fathalipour, Dehghan, Sirjani et al., Therapeutic strategies in the fight against COVID-19: from bench to bedside, Iran J Med Sci,
doi:/10.30476/IJMS.2021.92662.2396Alexander, Christopoulos, Davenport, The concise guide to pharmacology 2019/20: G protein-coupled receptors, Br J Pharmacol,
doi:/10.1111/bph.14748Carino, Moraca, Fiorillo, Hijacking SARS-CoV-2/ACE2 receptor interaction by natural and semi-synthetic steroidal agents acting on functional pockets on the receptor binding domain, Front Chem,
doi:/10.3389/fchem.2020.572885Colombo, Battezzati, Podda, Bettinardi, Giunta, Ursodeoxycholic acid for liver disease associated with cystic fibrosis: a double-blind multicenter trial. The Italian Group for the Study of Ursodeoxycholic Acid in Cystic Fibrosis, Hepatology,
doi:/10.1002/hep.510230627Crosignani, Battezzati, Setchell, Tauroursodeoxycholic acid for treatment of primary biliary cirrhosis. A dose-response study, Dig Dis Sci,
doi:/10.1007/BF02213140Dhawan, Saied, Mitra, Alhumaydhi, Emran et al., Omicron variant (B.1.1.529) and its sublineages: what do we know so far amid the emergence of recombinant variants of SARS-CoV-2?, Biomed Pharmacother,
doi:/10.1016/j.biopha.2022.113522Fan, Li, Zhang, Wan, Zhang et al., SARS-CoV-2 Omicron variant: recent progress and future perspectives, Signal Transduct Target Ther,
doi:/10.1038/s41392-022-00997-xGattinger, Ohradanova-Repic, Valenta, Importance, applications and features of assays measuring SARS-CoV-2 neutralizing antibodies, Int J Mol Sci,
doi:/10.3390/ijms24065352Gaziano, Giambartolomei, Pereira, Actionable druggable genome-wide Mendelian randomization identifies repurposing opportunities for COVID-19, Nat Med,
doi:/10.1038/s41591-021-01310-zGhoshal, Vasanth, Tejan, A guide to laboratory diagnosis of Corona Virus Disease-19 for the gastroenterologists, Indian J Gastroenterol,
doi:/10.1007/s12664-020-01082-3Hanafi, Mohamed, Sheikh, Kadir, Othman, Overview of bile acids signaling and perspective on the signal of ursodeoxycholic acid, the most hydrophilic bile acid, in the heart, Biomolecules,
doi:/10.3390/biom8040159Harding, Sharman, Faccenda, The IUPHAR/BPS guide to PHARMACOLOGY in 2018: updates and expansion to encompass the new guide to IMMUNOPHARMACOLOGY, Nucleic Acids Res,
doi:/10.1093/nar/gkx1121Imai, Iwatsuki-Horimoto, Hatta, Syrian hamsters as a small animal model for SARS-CoV-2 infection and countermeasure development, Proc Natl Acad Sci,
doi:/10.1073/pnas.2009799117Islam, Dhawan, Nafady, Understanding the omicron variant (B.1.1.529) of SARS-CoV-2: mutational impacts, concerns, and the possible solutions, Ann Med Surg (Lond),
doi:/10.1016/j.amsu.2022.103737Li, Hilgenfeld, Whitley, De Clercq, Therapeutic strategies for COVID-19: progress and lessons learned, Nat Rev Drug Discov,
doi:/10.1038/s41573-023-00672-yLong, Carius, Chavez, Clinical update on COVID-19 for the emergency clinician: presentation and evaluation, Am J Emerg Med,
doi:/10.1016/j.ajem.2022.01.028Niu, Li, Xu, Sun, Gan et al., Ursodeoxycholic acid protects against lung injury induced by fat embolism syndrome, J Cell Mol Med,
doi:/10.1111/jcmm.15985Park, Kim, Lee, Rapid emergence of the Omicron variant of severe acute respiratory syndrome coronavirus 2 in Korea, Ann Lab Med,
doi:/10.3343/alm.2023.43.2.211Sackmann, Pauletzki, Aydemir, Efficacy and safety of ursodeoxycholic acid for dissolution of gallstone fragments: comparison with the combination of ursodeoxycholic acid and chenodeoxycholic acid, Hepatology,
doi:/10.1002/hep.1840140630Willett, Grove, Maclean, The hyper-transmissible SARS-CoV-2 Omicron variant exhibits significant antigenic change, vaccine escape and a switch in cell entry mechanism, medRxiv,
doi:/10.1101/2022.01.03.21268111Zhao, Lu, Peng, SARS-CoV-2 Omicron variant shows less efficient replication and fusion activity when compared with Delta variant in TMPRSS2-expressed cells, Emerg Microbes Infect,
doi:/10.1080/22221751.2021.2023329Zhou, Mohlenberg, Thakor, Sensitivity to vaccines, therapeutic antibodies, and viral entry inhibitors and advances to counter the SARS-CoV-2 Omicron variant, Clin Microbiol Rev,
doi:/10.1128/cmr.00014-22{ 'indexed': {'date-parts': [[2024, 4, 5]], 'date-time': '2024-04-05T00:52:50Z', 'timestamp': 1712278370634},
'reference-count': 38,
'publisher': 'Wiley',
'issue': '2',
'license': [ { 'start': { 'date-parts': [[2024, 4, 4]],
'date-time': '2024-04-04T00:00:00Z',
'timestamp': 1712188800000},
'content-version': 'vor',
'delay-in-days': 3,
'URL': 'http://creativecommons.org/licenses/by-nc-nd/4.0/'}],
'content-domain': {'domain': ['bpspubs.onlinelibrary.wiley.com'], 'crossmark-restriction': True},
'published-print': {'date-parts': [[2024, 4]]},
'abstract': '<jats:title>Abstract</jats:title><jats:p>The SARS‐CoV‐2 caused COVID‐19 pandemic has posed a '
'global health hazard. While some vaccines have been developed, protection against viral '
'infection is not perfect because of the urgent approval process and the emergence of mutant '
'SARS‐CoV‐2 variants. Here, we employed UDCA as an FXR antagonist to regulate ACE2 expression, '
'which is one of the key pathways activated by SARS‐CoV‐2 Delta variant infection. UDCA is a '
'well‐known reagent of liver health supplements and the only clinically approved bile acid. In '
'this paper, we investigated the protective efficacy of UDCA on Omicron variation, since it '
'has previously been verified for protection against Delta variant. When co‐housing with an '
'Omicron variant‐infected hamster group resulted in spontaneous airborne transmission, the '
'UDCA pre‐supplied group was protected from weight loss relative to the non‐treated group at '
'4\u2009days post‐infection by more than 5%–10%. Furthermore, UDCA‐treated groups had a 3‐fold '
'decrease in ACE2 expression in nasal cavities, as well as reduced viral expressing genes in '
'the respiratory tract. Here, the data show that the UDCA serves an alternative option for '
'preventive drug, providing SARS‐CoV‐2 protection against not only Delta but also Omicron '
'variant. Our results of this study will help to propose drug‐repositioning of UDCA from liver '
'health supplement to preventive drug of SARS‐CoV‐2 infection.</jats:p>',
'DOI': '10.1002/prp2.1194',
'type': 'journal-article',
'created': {'date-parts': [[2024, 4, 4]], 'date-time': '2024-04-04T13:31:27Z', 'timestamp': 1712237487000},
'update-policy': 'http://dx.doi.org/10.1002/crossmark_policy',
'source': 'Crossref',
'is-referenced-by-count': 0,
'title': 'Ursodeoxycholic acid may protect from severe acute respiratory syndrome coronavirus 2 Omicron '
'variant by reducing angiotensin‐converting enzyme 2',
'prefix': '10.1002',
'volume': '12',
'author': [ { 'ORCID': 'http://orcid.org/0009-0001-2382-2854',
'authenticated-orcid': False,
'given': 'Kyungmin',
'family': 'Lee',
'sequence': 'first',
'affiliation': [ { 'name': 'Pharmaceutical Technology Center Daewoong Pharmaceutical Co., '
'Ltd Yongin‐si Gyeonggi‐do Republic of Korea'},
{ 'name': 'College of Pharmacy, Pusan National University Busan Republic '
'of Korea'}]},
{ 'ORCID': 'http://orcid.org/0009-0008-4507-7438',
'authenticated-orcid': False,
'given': 'Yujeong',
'family': 'Na',
'sequence': 'additional',
'affiliation': [ { 'name': 'Pharmaceutical Technology Center Daewoong Pharmaceutical Co., '
'Ltd Yongin‐si Gyeonggi‐do Republic of Korea'}]},
{ 'ORCID': 'http://orcid.org/0009-0009-3380-1828',
'authenticated-orcid': False,
'given': 'Minjin',
'family': 'Kim',
'sequence': 'additional',
'affiliation': [ { 'name': 'Drug Discovery Center Daewoong Pharmaceutical Co., Ltd '
'Yongin‐si Gyeonggi‐do Republic of Korea'}]},
{ 'ORCID': 'http://orcid.org/0009-0007-4042-4720',
'authenticated-orcid': False,
'given': 'Dongjin',
'family': 'Lee',
'sequence': 'additional',
'affiliation': [ { 'name': 'Pharmaceutical Technology Center Daewoong Pharmaceutical Co., '
'Ltd Yongin‐si Gyeonggi‐do Republic of Korea'}]},
{ 'ORCID': 'http://orcid.org/0009-0000-4360-6641',
'authenticated-orcid': False,
'given': 'Jongseo',
'family': 'Choi',
'sequence': 'additional',
'affiliation': [ { 'name': 'Pharmaceutical Technology Center Daewoong Pharmaceutical Co., '
'Ltd Yongin‐si Gyeonggi‐do Republic of Korea'}]},
{ 'ORCID': 'http://orcid.org/0009-0006-4528-2816',
'authenticated-orcid': False,
'given': 'Gwanyoung',
'family': 'Kim',
'sequence': 'additional',
'affiliation': [ { 'name': 'Pharmaceutical Technology Center Daewoong Pharmaceutical Co., '
'Ltd Yongin‐si Gyeonggi‐do Republic of Korea'}]},
{ 'ORCID': 'http://orcid.org/0000-0001-9426-5015',
'authenticated-orcid': False,
'given': 'Min‐Soo',
'family': 'Kim',
'sequence': 'additional',
'affiliation': [ { 'name': 'College of Pharmacy, Pusan National University Busan Republic '
'of Korea'}]}],
'member': '311',
'published-online': {'date-parts': [[2024, 4, 4]]},
'reference': [ {'key': 'e_1_2_12_2_1', 'doi-asserted-by': 'publisher', 'DOI': '10.3390/ijms24065352'},
{'key': 'e_1_2_12_3_1', 'doi-asserted-by': 'publisher', 'DOI': '10.1038/s41573-023-00672-y'},
{'key': 'e_1_2_12_4_1', 'doi-asserted-by': 'publisher', 'DOI': '10.1038/s41586-020-2286-9'},
{ 'key': 'e_1_2_12_5_1',
'doi-asserted-by': 'publisher',
'DOI': '10.30476/IJMS.2021.92662.2396'},
{'key': 'e_1_2_12_6_1', 'doi-asserted-by': 'publisher', 'DOI': '10.1038/s41579-023-00878-2'},
{ 'key': 'e_1_2_12_7_1',
'doi-asserted-by': 'publisher',
'DOI': '10.1016/S0262-4079(21)02140-0'},
{ 'key': 'e_1_2_12_8_1',
'doi-asserted-by': 'publisher',
'DOI': '10.1016/j.biopha.2022.113522'},
{'key': 'e_1_2_12_9_1', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.amsu.2022.103737'},
{'key': 'e_1_2_12_10_1', 'doi-asserted-by': 'publisher', 'DOI': '10.3343/alm.2023.43.2.211'},
{'key': 'e_1_2_12_11_1', 'doi-asserted-by': 'publisher', 'DOI': '10.1128/cmr.00014-22'},
{ 'key': 'e_1_2_12_12_1',
'doi-asserted-by': 'publisher',
'DOI': '10.1038/s41586-022-05594-0'},
{ 'key': 'e_1_2_12_13_1',
'doi-asserted-by': 'publisher',
'DOI': '10.1038/s41591-021-01310-z'},
{'key': 'e_1_2_12_14_1', 'doi-asserted-by': 'publisher', 'DOI': '10.1038/s41586-020-2012-7'},
{ 'key': 'e_1_2_12_15_1',
'doi-asserted-by': 'publisher',
'DOI': '10.1161/01.ATV.0000178994.21828.a7'},
{'key': 'e_1_2_12_16_1', 'doi-asserted-by': 'publisher', 'DOI': '10.3389/fchem.2020.572885'},
{'key': 'e_1_2_12_17_1', 'doi-asserted-by': 'publisher', 'DOI': '10.3390/biom8040159'},
{'key': 'e_1_2_12_18_1', 'doi-asserted-by': 'publisher', 'DOI': '10.1007/BF02213140'},
{'key': 'e_1_2_12_19_1', 'doi-asserted-by': 'publisher', 'DOI': '10.1002/hep.510230627'},
{'key': 'e_1_2_12_20_1', 'doi-asserted-by': 'publisher', 'DOI': '10.1002/hep.1840140630'},
{'key': 'e_1_2_12_21_1', 'doi-asserted-by': 'publisher', 'DOI': '10.1111/jcmm.15985'},
{ 'key': 'e_1_2_12_22_1',
'doi-asserted-by': 'publisher',
'DOI': '10.1111/j.1872-034X.2007.00297.x'},
{'key': 'e_1_2_12_23_1', 'doi-asserted-by': 'publisher', 'DOI': '10.1073/pnas.2009799117'},
{'key': 'e_1_2_12_24_1', 'doi-asserted-by': 'publisher', 'DOI': '10.1093/nar/gkx1121'},
{'key': 'e_1_2_12_25_1', 'doi-asserted-by': 'publisher', 'DOI': '10.1111/bph.14748'},
{ 'key': 'e_1_2_12_26_1',
'doi-asserted-by': 'publisher',
'DOI': '10.1038/d41573-022-00074-6'},
{ 'key': 'e_1_2_12_27_1',
'doi-asserted-by': 'publisher',
'DOI': '10.1038/s41564-022-01241-6'},
{ 'key': 'e_1_2_12_28_1',
'doi-asserted-by': 'crossref',
'unstructured': 'WillettBJ GroveJ MacLeanOA et\xa0al.The hyper‐transmissible SARS‐CoV‐2 '
'Omicron variant exhibits significant antigenic change vaccine escape and '
'a switch in cell entry mechanism.medRxiv. 2022:2022.01.03.21268111. '
'doi:10.1101/2022.01.03.21268111',
'DOI': '10.1101/2022.01.03.21268111'},
{ 'key': 'e_1_2_12_29_1',
'doi-asserted-by': 'publisher',
'DOI': '10.1016/j.ajem.2022.01.028'},
{ 'key': 'e_1_2_12_30_1',
'doi-asserted-by': 'publisher',
'DOI': '10.1038/s41392-022-00997-x'},
{ 'key': 'e_1_2_12_31_1',
'doi-asserted-by': 'publisher',
'DOI': '10.1038/s41586-022-04474-x'},
{ 'key': 'e_1_2_12_32_1',
'doi-asserted-by': 'publisher',
'DOI': '10.1080/22221751.2021.2023329'},
{ 'key': 'e_1_2_12_33_1',
'doi-asserted-by': 'publisher',
'DOI': '10.1038/s41586-022-04442-5'},
{ 'key': 'e_1_2_12_34_1',
'doi-asserted-by': 'publisher',
'DOI': '10.1007/s12664-020-01082-3'},
{'key': 'e_1_2_12_35_1', 'doi-asserted-by': 'publisher', 'DOI': '10.12771/emj.2021.44.1.1'},
{'key': 'e_1_2_12_36_1', 'doi-asserted-by': 'publisher', 'DOI': '10.1021/acsnano.0c02624'},
{'key': 'e_1_2_12_37_1', 'doi-asserted-by': 'publisher', 'DOI': '10.1038/s41590-020-0778-2'},
{'key': 'e_1_2_12_38_1', 'doi-asserted-by': 'publisher', 'DOI': '10.3389/fphar.2020.579330'},
{'key': 'e_1_2_12_39_1', 'doi-asserted-by': 'publisher', 'DOI': '10.1128/JVI.02012-06'}],
'container-title': 'Pharmacology Research & Perspectives',
'original-title': [],
'language': 'en',
'link': [ { 'URL': 'https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1002/prp2.1194',
'content-type': 'unspecified',
'content-version': 'vor',
'intended-application': 'similarity-checking'}],
'deposited': { 'date-parts': [[2024, 4, 4]],
'date-time': '2024-04-04T13:31:32Z',
'timestamp': 1712237492000},
'score': 1,
'resource': {'primary': {'URL': 'https://bpspubs.onlinelibrary.wiley.com/doi/10.1002/prp2.1194'}},
'subtitle': [],
'short-title': [],
'issued': {'date-parts': [[2024, 4]]},
'references-count': 38,
'journal-issue': {'issue': '2', 'published-print': {'date-parts': [[2024, 4]]}},
'alternative-id': ['10.1002/prp2.1194'],
'URL': 'http://dx.doi.org/10.1002/prp2.1194',
'relation': {},
'ISSN': ['2052-1707', '2052-1707'],
'subject': ['General Pharmacology, Toxicology and Pharmaceutics', 'Neurology'],
'container-title-short': 'Pharmacology Res & Perspec',
'published': {'date-parts': [[2024, 4]]},
'assertion': [ { 'value': '2024-01-05',
'order': 0,
'name': 'received',
'label': 'Received',
'group': {'name': 'publication_history', 'label': 'Publication History'}},
{ 'value': '2024-03-09',
'order': 1,
'name': 'accepted',
'label': 'Accepted',
'group': {'name': 'publication_history', 'label': 'Publication History'}},
{ 'value': '2024-04-04',
'order': 2,
'name': 'published',
'label': 'Published',
'group': {'name': 'publication_history', 'label': 'Publication History'}}]}
