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

Abstract

Angiotensin-converting enzyme 2 (ACE2) is a receptor for cell entry of SARS-CoV-2, and recombinant soluble ACE2 protein inhibits SARS-CoV-2 infection as a decoy. ACE2 is the carboxypeptidase to degrade angiotensin II (Ang II) to angiotensin 1-7 and improves the pathologies of cardiovascular disease and acute lung injury. To address whether the carboxypeptidase enzymatic activity of ACE2 is protective against COVID-19, we investigated the effects of B38-CAP, an ACE2-like enzyme, on SARS-CoV-2-induced lung injury. Expression of ACE2 protein was significantly downregulated in the lungs of SARS-CoV-2-infected hamsters. Recombinant S1 domain or receptor-binding domain (RBD) of the SARS-CoV-2 Spike protein also directly downregulated ACE2 expression and elevated Ang II levels and considerably worsened acid-induced lung injury in hamsters. Treatment with B38-CAP downregulated Spike RBD-induced high Ang II levels, severe inflammation and pulmonary edema through its ACE2-like enzymatic activity. Consistently, elevated cytokine mRNA levels and impaired lung functions were improved by B38-CAP treatment. Moreover, in SARS-CoV-2-infected humanized ACE2 transgenic mice, B38-CAP significantly improved the pathologies of lung injury, alleviated the cytokine storms and downregulated viral RNA levels. These results provide the first experimental in vivo evidence that increasing ACE2-like enzymatic activity is a potential and powerful therapeutic strategy for lung pathologies in COVID-19.

Engineered ACE2-Fc counters murine lethal SARS-CoV-2 infection through direct neutralization and Fc-effector activities

“…Multiple studies confirm the beneficial effect of ACE2 enzymatic activity in anti–SARS-CoV-2 activities of the ACE2–based therapeutics ( 11 , 59 ). Active sACE2 and ACE2-like enzymes were shown to effectively reduce the vasopressor Ang II in plasma and attenuate acute lung injury caused by SARS-CoV-1 and SARS-CoV-2 by rebalancing renin-angiotensin homeostasis when membrane-bound ACE2 has been stripped and down-regulated by S binding ( 11 , 12 , 42 ). Thus, compared to inactive forms, engineered ACE2 antivirals with intrinsic Ang II–converting activity are expected to be a better therapeutic option, which can not only block viral spread but also modulate the RAS system to prevent lung failure in patients with SARS-CoV-2.…”

“…Multiple studies confirm the beneficial effect of ACE2 enzymatic activity in anti–SARS-CoV-2 activities of the ACE2–based therapeutics ( 11 , 59 ). Active sACE2 and ACE2-like enzymes were shown to effectively reduce the vasopressor Ang II in plasma and attenuate acute lung injury caused by SARS-CoV-1 and SARS-CoV-2 by rebalancing renin-angiotensin homeostasis when membrane-bound ACE2 has been stripped and down-regulated by S binding ( 11 , 12 , 42 ).…”

“…Concomitant with the viral load reduction was a profound decrease of Ang II and a proportional increase of the ACE2 products Ang 1-7 and Ang 1-9 in the plasma. Although compelling evidence confirms ACE2 enzymatic activity as an important component of the therapeutic activity of ACE2-Fc, due to its protective action against SARS-CoV-1– and SARS-CoV-2–induced acute lung injury ( 11 , 12 ), ACE2-inactivated mutants with enhanced affinities for SARS-CoV-2 RBD and increased neutralization potencies have been developed ( 13 ) as possible alternative options.…”

Targeting thromboinflammation in COVID-19 – A narrative review of the potential of C1 inhibitor to prevent disease progression

“…Interestingly, expression of ACE2 and its enzymatic activity is decreased in SARS-CoV and inflammatory conditions ( Guy et al, 1992 , Kuba et al, 2005 , Sodhi et al, 2018 ) and hence one may speculate that the interaction of SARS-CoV-2 with ACE2 may impair the function of ACE2 leading to a relative abundance of active bradykinin metabolites with subsequent B1 receptor activation, local pulmonary edema and exacerbated lung injury ( Sodhi et al, 2018 ). Indeed, a reduced ACE2 expression in hamster lungs after SARS-CoV-2 infection was recently demonstrated ( Yamaguchi et al, 2021 ). In a recently published study, a soluble ACE2 protein with increased binding to the spike protein has shown protective capabilities with regards to lung and kidney injury ( Hassler et al, 2022 ).…”

Optimization of blood pressure control, organ protection and metabolic disorders using a fixed-dose combination of lisinopril+amlodipine+rosuvastatin in hypertensive patients after COVID-19

“…Говоря о терапии статинами, следует отметить, что, с одной стороны, статины повышают экспрес- Вирус SARS-CoV-2 проникает в дыхательные пути и связывается с клеткой мишенью (альвеолярные клетки 2 типа), имеющие рецепторы ангиотензинпревращающего фермента II типа (ACE2) [1]. Гипотеза о причастности ренин-ангиотензиновой системы к воспалительному процессу, спровоцированному проникновением SARS-CoV-2 в ткани (в первую очередь в легкие), учитывает, что потеря функции ACE2 вызывает дисбаланс, повышая концентрацию ангиотензина II в тканях (провоспалительный эффект) и одновременно снижая уровень ангиотензина 1-7 (противовоспалительное действие) [2,3]. Это приводит к высвобождению провоспалительных цитокинов [4,5]…”