ACE2-like carboxypeptidase B38-CAP protects from SARS-CoV-2-induced lung injury

Minato, Takafumi; Hoshizaki, Midori; Yamaguchi, Tomokazu; An, Jianbo; Niiyama, Mayumi; Nirasawa, Satoru; Asaka, Mitsuhiro; Chan, Jasper Fuk‐Woo; Imai, Masaki; Takahashi, Saori; Utsumi, Daichi; Poon, Vincent Kwok-Man; Yasuhara, Atsuhiro; Chan, Chris; Motoyama, Satoru; Nagata, Satoshi; Penninger, Josef; Kamada, Haruhiko; Yuen, Kwok‐Yung; Kawaoka, Yoshihiro; Yasutomi, Yasuhiro; Imai, Yumiko; Kuba, Keiji

doi:10.21203/rs.3.rs-124634/v1

Cited by 2 publications

(2 citation statements)

References 32 publications

(59 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It should be noted that as part of SARS-CoV-2 infection and internalization of the ACE2-SARS-CoV-2 complex, there may be depletion of cell membrane–bound full-length ACE2 15 , 73 , 74 . This, in turn, can contribute to lung injury because of the accumulation of angiotensin II (Ang II) and des-Arg9 bradykinin 15 , 59 , 74 – 77 .…”

Section: Discussionmentioning

confidence: 99%

“…It should be noted that as part of SARS-CoV-2 infection and internalization of the ACE2-SARS-CoV-2 complex, there may be depletion of cell membrane-bound full-length ACE2. 15,73,74 This, in turn, can contribute to lung injury because of the accumulation of angiotensin II (Ang II) and des-Arg9 bradykinin. 15,59,[74][75][76][77] If this is the case, further therapeutic benefit of administering soluble ACE2 protein ought to result from providing ACE2 activity.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

A Novel Soluble ACE2 Protein Provides Lung and Kidney Protection in Mice Susceptible to Lethal SARS-CoV-2 Infection

Hassler

Wysocki

Gelarden

et al. 2022

JASN

View full text Add to dashboard Cite

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 prior to 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 6/7 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 virus was absent in the kidneys. However, some untreated animals had variable degrees of kidney proximal tubular injury with increased NGAL and TUNEL staining indicating attenuation of the proximal tubular brush border. In contrast, viral titers in the lung and brain were reduced or non-detectable in mice that received ACE2 1-618 DDCABD, 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 causes severe lung injury as well as variable degrees of moderate proximal tubular injury.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

A Novel Soluble ACE2 Protein Provides Lung and Kidney Protection in Mice Susceptible to Lethal SARS-CoV-2 Infection

Hassler

Wysocki

Gelarden

et al. 2022

JASN

View full text Add to dashboard Cite

show abstract

Telmisartan for treatment of Covid-19 patients: An open multicenter randomized clinical trial

et al. 2021

View full text Add to dashboard Cite

Background: Angiotensin receptor blockers (ARBs), such as telmisartan, have been postulated to treat Covid-19-induced lung inflammation. Methods: This is a parallel-group, randomized, two-arm, open-label, adaptive, multicenter superiority trial with 1:1 allocation ratio. Participants included patients from 18 years of age hospitalized with Covid-19 with 4 or fewer days since symptom onset enrolled at a university and a community hospital in Buenos Aires, Argentina. Exclusion criteria included prior intensive care unit (ICU) admission and use of ARBs/angiotensin converting enzyme inhibitors at randomization. Control arm received standard care alone and treatment arm telmisartan 80 mg twice daily for 14 days. Primary outcomes were C-reactive protein (CRP) plasma levels at day 5 and 8 after randomization. Secondary outcomes included time to discharge within 15 days, admission to ICU and death at 15-and 30-days. NCT04355936 (Completed). Findings: A pragmatic decision to end the study before the third interim analysis was made on Oct. 30th due to sharp reduction in recruitment. A total of 162 patients were randomized. 158 patients enrolled between May 14 and October 30 2020, were included in the analysis, 80 in the standard care and 78 in the telmisartan added to standard care group. Baseline absolute CRP serum levels were 5.53 § 6.19 mg/dL (95% CI 6.91 to 4.15, n = 80) and 9.04 § 7.69 (95% CI 9.04 to 10.82, n = 74) in the standard care and telmisartan added to standard care groups, respectively. Day 5 control-group CRP levels were 6.06 § 6.95 mg/dL (95% CI 7.79À4.35, n = 66) while telmisartan group were 3.83 § 5.08 mg/dL (95% CI 5.08À2.59, n = 66, p = 0.038). Day 8 CRP levels were 6.30 § 8.19 mg/dL (95% CI 8.79À3.81, n = 44) and 2.37 § 3.47 mg/dL (95% CI 3.44À1.30, n = 43, p = 0.0098) in the control and telmisartan groups, respectively (all values expressed as mean § SD). Kaplan-Meier analysis showed that telmisartan-treated patients had a lower median time-to-discharge (control=15 days; telmisartan=9 days). Death by day 30 was reduced in the telmisartan-treated group (control 22.54%,

show abstract

ACE2-like carboxypeptidase B38-CAP protects from SARS-CoV-2-induced lung injury

Cited by 2 publications

References 32 publications

A Novel Soluble ACE2 Protein Provides Lung and Kidney Protection in Mice Susceptible to Lethal SARS-CoV-2 Infection

A Novel Soluble ACE2 Protein Provides Lung and Kidney Protection in Mice Susceptible to Lethal SARS-CoV-2 Infection

Telmisartan for treatment of Covid-19 patients: An open multicenter randomized clinical trial

Contact Info

Product

Resources

About