Clinically Approved Antiviral Drug in an Orally Administrable Nanoparticle for COVID-19
Bapurao Surnar, Mohammad Z Kamran, Anuj S Shah, Shanta Dhar
ACS Pharmacology & Translational Science, doi:10.1021/acsptsci.0c00179
There is urgent therapeutic need for COVID-19, a disease for which there are currently no widely effective approved treatments and the emergency use authorized drugs do not result in significant and widespread patient improvement. The food and drug administration-approved drug ivermectin has long been shown to be both antihelmintic agent and a potent inhibitor of viruses such as Yellow Fever Virus. In this study, we highlight the potential of ivermectin packaged in an orally administrable nanoparticle that could serve as a vehicle to deliver a more potent therapeutic antiviral dose and demonstrate its efficacy to decrease expression of viral spike protein and its receptor angiotensin-converting enzyme 2 (ACE2), both of which are keys to lowering disease transmission rates. We also report that the targeted nanoparticle delivered ivermectin is able to inhibit the nuclear transport activities mediated through proteins such as importin α/β1 heterodimer as a possible mechanism of action. This study sheds light on ivermectin-loaded, orally administrable, biodegradable nanoparticles to be a potential treatment option for the novel coronavirus through a multilevel inhibition. As both ACE2 targeting and the presence of spike protein are features shared among this class of virus, this platform technology has the potential to serve as a therapeutic tool not only for COVID-19 but for other coronavirus strains as well.
Notes The authors declare no competing financial interest.
■ ACKNOWLEDGMENTS This work was supported by the Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine. We thank Shrita Sarkar for her help for the illustration of Figure 1 and Dr. Nagesh Kolishetti for helpful discussion.
References
Dashraath, Wong, Lim, Lim, Li et al., Coronavirus disease 2019 (COVID-19) pandemic and pregnancy, Am. J. Obstet. Gynecol,
doi:10.1016/j.ajog.2020.03.021Elkassaby, Ivermectin uptake and distribution in the plasma and tissue of Sudanese and Mexican patients infected with Onchocerca volvulus, Trop. Med. Parasitol
Gheblawi, Wang, Viveiros, Nguyen, Zhong, None
Heidary, Gharebaghi, Ivermectin: a systematic review from antiviral effects to COVID-19 complementary regimen, J. Antibiot,
doi:10.1038/s41429-020-0336-zLi, He, Zhang, Ran, Wang et al., Assessing ACE2 expression patterns in lung tissues in the pathogenesis of COVID-19, J. Autoimmun,
doi:10.1016/j.jaut.2020.102463Mastrangelo, Pezzullo, De Burghgraeve, Kaptein, Pastorino et al., Ivermectin Is a Potent Inhibitor of Flavivirus Replication Specifically Targeting NS3 Helicase Activity: New Prospects for an Old Drug, J. Antimicrob. Chemother,
doi:10.1093/jac/dks147Mcgonagle, Sharif, O'regan, Bridgewood, The Role of Cytokines including Interleukin-6 in COVID-19 induced Pneumonia and Macrophage Activation Syndrome-Like Disease, Autoimmun. Rev,
doi:10.1016/j.autrev.2020.102537Merad, Martin, Pathological inflammation in patients with COVID-19: a key role for monocytes and macrophages, Nat. Rev. Immunol,
doi:10.1038/s41577-020-0331-4Ou, Liu, Lei, Li, Mi et al., Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV, Nat. Commun,
doi:10.1038/s41467-020-15562-9Pandey, Khan, Kumar, Srivastava, Jha, Screening of Potent Inhibitors Against 2019 Novel Coronavirus (Covid-19) from Alliumsativum and Allium cepa: An In Silico Approach, Biointerface Res. Appl. Chem,
doi:10.33263/BRIAC111.79817993Pandey, Khan, Rana, Srivastava, Jha et al., A Drug Repurposing Approach Towards Elucidating the Potential of Flavonoids as COVID-19 Spike Protein Inhibitors, Biointerface Res. Appl. Chem,
doi:10.33263/BRIAC111.84828501Qin, Zhou, Hu, Zhang, Yang et al., Dysregulation of immune response in patients with COVID-19 in Wuhan, China, Clin. Infect. Dis,
doi:10.1093/cid/ciaa248Rowland, Chauhan, Fang, Pekosz, Kerrigan et al., Intracellular localization of the severe acute respiratory syndrome coronavirus nucleocapsid protein: absence of nucleolar accumulation during infection and after expression as a recombinant protein in Vero cells, J. Virol,
doi:10.1128/JVI.79.17.11507-11512.2005Singh, Chaubey, Chen, Suravajhala, Decoding SARS-CoV-2 hijacking of host mitochondria in COVID-19 pathogenesis, Am. J. Physiol Cell Physiol,
doi:10.1152/ajpcell.00224.2020Sungnak, Huang, Becavin, Berg, Queen et al., None
Surnar, Kamran, Shah, Basu, Kolishetti et al., Orally Administrable Therapeutic Synthetic Nanoparticle for Zika Virus, ACS Nano,
doi:10.1021/acsnano.9b02807Timani, Liao, Ye, Zeng, Liu et al., Nuclear/ nucleolar localization properties of C-terminal nucleocapsid protein of SARS coronavirus, Virus Res,
doi:10.1016/j.virusres.2005.05.007Turner, Raizada, Grant, Oudit, Angiotensin-Converting Enzyme 2: SARS-CoV-2 Receptor and Regulator of the Renin-Angiotensin System, Circ. Res,
doi:10.1161/CIRCRESAHA.120.317015Wagstaff, Rawlinson, Hearps, Jans, None
Wagstaff, Sivakumaran, Heaton, Harrich, Jans, Ivermectin is a specific inhibitor of importin alpha/beta-mediated nuclear import able to inhibit replication of HIV-1 and dengue virus, Biochem. J,
doi:10.1042/BJ20120150Wang, Du, Huang, Wei, Wu et al., The Pseudorabies Virus DNA Polymerase Accessory Subunit UL42 Directs Nuclear Transport of the Holoenzyme, Front. Microbiol,
doi:10.3389/fmicb.2016.00124Wulan, Heydet, Walker, Gahan, Ghildyal, Nucleocytoplasmic transport of nucleocapsid proteins of enveloped RNA viruses, Front. Microbiol,
doi:10.3389/fmicb.2015.00553Yan, Zhang, Li, Xia, Guo et al., Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2, Science,
doi:10.1126/science.abb2762Yang, Atkinson, Wang, Lee, Bogoyevitch et al., The broad spectrum antiviral ivermectin targets the host nuclear transport importin alpha/ beta1 heterodimer, Antiviral Res,
doi:10.1016/j.antiviral.2020.104760Zhang, Penninger, Li, Zhong, Slutsky, Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target, Intensive Care Med,
doi:10.1007/s00134-020-05985-9{ 'indexed': {'date-parts': [[2024, 3, 25]], 'date-time': '2024-03-25T10:19:55Z', 'timestamp': 1711361995868},
'reference-count': 27,
'publisher': 'American Chemical Society (ACS)',
'issue': '6',
'license': [ { 'start': { 'date-parts': [[2020, 12, 1]],
'date-time': '2020-12-01T00:00:00Z',
'timestamp': 1606780800000},
'content-version': 'stm-asf',
'delay-in-days': 0,
'URL': 'https://doi.org/10.15223/policy-001'},
{ 'start': { 'date-parts': [[2020, 12, 1]],
'date-time': '2020-12-01T00:00:00Z',
'timestamp': 1606780800000},
'content-version': 'stm-asf',
'delay-in-days': 0,
'URL': 'https://doi.org/10.15223/policy-009'},
{ 'start': { 'date-parts': [[2020, 12, 1]],
'date-time': '2020-12-01T00:00:00Z',
'timestamp': 1606780800000},
'content-version': 'stm-asf',
'delay-in-days': 0,
'URL': 'https://doi.org/10.15223/policy-017'}],
'funder': [{'name': 'Sylvester Comprehensive Cancer Center, University of Miami'}],
'content-domain': {'domain': [], 'crossmark-restriction': False},
'published-print': {'date-parts': [[2020, 12, 11]]},
'DOI': '10.1021/acsptsci.0c00179',
'type': 'journal-article',
'created': {'date-parts': [[2020, 12, 1]], 'date-time': '2020-12-01T14:20:14Z', 'timestamp': 1606832414000},
'page': '1371-1380',
'source': 'Crossref',
'is-referenced-by-count': 30,
'title': 'Clinically Approved Antiviral Drug in an Orally Administrable Nanoparticle for COVID-19',
'prefix': '10.1021',
'volume': '3',
'author': [ { 'ORCID': 'http://orcid.org/0000-0001-5997-3120',
'authenticated-orcid': True,
'given': 'Bapurao',
'family': 'Surnar',
'sequence': 'first',
'affiliation': []},
{'given': 'Mohammad Z.', 'family': 'Kamran', 'sequence': 'additional', 'affiliation': []},
{'given': 'Anuj S.', 'family': 'Shah', 'sequence': 'additional', 'affiliation': []},
{ 'ORCID': 'http://orcid.org/0000-0003-3042-5272',
'authenticated-orcid': True,
'given': 'Shanta',
'family': 'Dhar',
'sequence': 'additional',
'affiliation': []}],
'member': '316',
'published-online': {'date-parts': [[2020, 12, 1]]},
'reference': [ {'key': 'ref1/cit1', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.jpha.2020.03.001'},
{'key': 'ref2/cit2', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.clim.2020.108427'},
{'key': 'ref3/cit3', 'doi-asserted-by': 'publisher', 'DOI': '10.1161/CIRCRESAHA.120.317015'},
{'key': 'ref4/cit4', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.jaut.2020.102463'},
{'key': 'ref5/cit5', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.autrev.2020.102537'},
{'key': 'ref6/cit6', 'doi-asserted-by': 'publisher', 'DOI': '10.1038/s41577-020-0331-4'},
{'key': 'ref7/cit7', 'doi-asserted-by': 'publisher', 'DOI': '10.1038/s41467-020-15562-9'},
{'key': 'ref8/cit8', 'doi-asserted-by': 'publisher', 'DOI': '10.1093/cid/ciaa248'},
{'key': 'ref9/cit9', 'doi-asserted-by': 'publisher', 'DOI': '10.1038/s41591-020-0868-6'},
{'key': 'ref10/cit10', 'doi-asserted-by': 'publisher', 'DOI': '10.1126/science.abb2762'},
{'key': 'ref11/cit11', 'doi-asserted-by': 'publisher', 'DOI': '10.1007/s00134-020-05985-9'},
{'key': 'ref12/cit12', 'doi-asserted-by': 'publisher', 'DOI': '10.33263/BRIAC111.79817993'},
{'key': 'ref13/cit13', 'doi-asserted-by': 'publisher', 'DOI': '10.33263/BRIAC111.84828501'},
{'key': 'ref14/cit14', 'doi-asserted-by': 'publisher', 'DOI': '10.1093/jac/dks147'},
{'key': 'ref15/cit15', 'doi-asserted-by': 'publisher', 'DOI': '10.1038/s41429-020-0336-z'},
{'key': 'ref16/cit16', 'doi-asserted-by': 'publisher', 'DOI': '10.3389/fmicb.2016.00124'},
{'key': 'ref17/cit17', 'doi-asserted-by': 'publisher', 'DOI': '10.1021/acsnano.9b02807'},
{ 'issue': '2',
'key': 'ref18/cit18',
'first-page': '79',
'volume': '42',
'author': 'Elkassaby M. H.',
'year': '1991',
'journal-title': 'Trop. Med. Parasitol.'},
{'key': 'ref19/cit19', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.ajog.2020.03.021'},
{ 'key': 'ref20/cit20',
'doi-asserted-by': 'publisher',
'DOI': '10.1016/j.antiviral.2020.104787'},
{ 'key': 'ref21/cit21',
'doi-asserted-by': 'publisher',
'DOI': '10.1128/JVI.79.17.11507-11512.2005'},
{ 'key': 'ref22/cit22',
'doi-asserted-by': 'publisher',
'DOI': '10.1016/j.virusres.2005.05.007'},
{'key': 'ref23/cit23', 'doi-asserted-by': 'publisher', 'DOI': '10.1177/1087057110390360'},
{'key': 'ref24/cit24', 'doi-asserted-by': 'publisher', 'DOI': '10.1042/BJ20120150'},
{'key': 'ref25/cit25', 'doi-asserted-by': 'publisher', 'DOI': '10.3389/fmicb.2015.00553'},
{ 'key': 'ref26/cit26',
'doi-asserted-by': 'publisher',
'DOI': '10.1016/j.antiviral.2020.104760'},
{'key': 'ref27/cit27', 'doi-asserted-by': 'publisher', 'DOI': '10.1152/ajpcell.00224.2020'}],
'container-title': 'ACS Pharmacology & Translational Science',
'original-title': [],
'language': 'en',
'link': [ { 'URL': 'https://pubs.acs.org/doi/pdf/10.1021/acsptsci.0c00179',
'content-type': 'unspecified',
'content-version': 'vor',
'intended-application': 'similarity-checking'}],
'deposited': { 'date-parts': [[2023, 4, 27]],
'date-time': '2023-04-27T06:14:43Z',
'timestamp': 1682576083000},
'score': 1,
'resource': {'primary': {'URL': 'https://pubs.acs.org/doi/10.1021/acsptsci.0c00179'}},
'subtitle': [],
'short-title': [],
'issued': {'date-parts': [[2020, 12, 1]]},
'references-count': 27,
'journal-issue': {'issue': '6', 'published-print': {'date-parts': [[2020, 12, 11]]}},
'alternative-id': ['10.1021/acsptsci.0c00179'],
'URL': 'http://dx.doi.org/10.1021/acsptsci.0c00179',
'relation': {},
'ISSN': ['2575-9108', '2575-9108'],
'subject': [],
'container-title-short': 'ACS Pharmacol. Transl. Sci.',
'published': {'date-parts': [[2020, 12, 1]]}}
