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1.
J Am Soc Nephrol ; 33(7): 1293-1307, 2022 07.
Article in English | MEDLINE | ID: covidwho-1799028

ABSTRACT

BACKGROUND: Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) uses full-length angiotensin converting enzyme 2 (ACE2) as a main receptor to enter target cells. The goal of this study was to demonstrate the preclinical efficacy of a novel soluble ACE2 protein with increased duration of action and binding capacity in a lethal mouse model of COVID-19. METHODS: A human soluble ACE2 variant fused with an albumin binding domain (ABD) was linked via a dimerization motif hinge-like 4-cysteine dodecapeptide (DDC) to improve binding capacity to SARS-CoV-2. This novel soluble ACE2 protein (ACE2-1-618-DDC-ABD) was then administered intranasally and intraperitoneally to mice before intranasal inoculation of SARS-CoV-2 and then for two additional days post viral inoculation. RESULTS: Untreated animals became severely ill, and all had to be humanely euthanized by day 6 or 7 and had pulmonary alveolar hemorrhage with mononuclear infiltrates. In contrast, all but one mouse infected with a lethal dose of SARS-CoV-2 that received ACE2-1-618-DDC-ABD survived. In the animals inoculated with SARS-CoV-2 that were untreated, viral titers were high in the lungs and brain, but viral titers were absent in the kidneys. Some untreated animals, however, had variable degrees of kidney proximal tubular injury as shown by attenuation of the proximal tubular brush border and increased NGAL and TUNEL staining. Viral titers in the lung and brain were reduced or nondetectable in mice that received ACE2-1-618-DDC-ABD, and the animals developed only moderate disease as assessed by a near-normal clinical score, minimal weight loss, and improved lung and kidney injury. CONCLUSIONS: This study demonstrates the preclinical efficacy of a novel soluble ACE2 protein, termed ACE2-1-618-DDC-ABD, in a lethal mouse model of SARS-CoV-2 infection that develops severe lung injury and variable degrees of moderate kidney proximal tubular injury.


Subject(s)
Angiotensin-Converting Enzyme 2 , COVID-19 , Angiotensin-Converting Enzyme 2/therapeutic use , Animals , COVID-19/therapy , Kidney/virology , Lung/virology , Mice , SARS-CoV-2
2.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-305642

ABSTRACT

Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 has led to over 200,000 deaths thus far. We screened a library of approved antiviral drugs against the two SARS-CoV-2 proteases, 3C-like/main protease (3CLpro/Mpro) and papain-like protease (PLpro), which are essential for viral replication and attractive drug targets. Three HCV protease inhibitors were tested and found to inhibit 3CLpro and PLpro enzymes from Alpha-, Beta- and Gamma-coronaviruses. Anti-HIV drugs had no activity. Boceprevir and telaprevir inhibited 3CLpro, with boceprevir inhibiting eight of nine coronavirus 3CLpro enzymes tested including from SARS-CoV-2, MERS and SARS-CoV. Asunaprevir inhibited PLpro from SARS-CoV-2 and four other coronaviruses. The 1.4 Å X-ray structure of boceprevir bound to 3CLpro was determined to explain its broad-spectrum activity and guide structure-based design of inhibitors of multiple coronaviruses.Authors Brandon J. Anson, Mackenzie E. Chapman, and Emma K. Lendy contributed equally to this work.

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