Abstract
In this study, we developed angiotensin-converting enzyme 2 (ACE2)-specific, peptide-derived 68Ga-labeled radiotracers, motivated by the hypotheses that ACE2 is an important determinant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) susceptibility and that modulation of ACE2 in coronavirus disease 2019 (COVID-19) drives severe organ injury. Methods: A series of NOTA-conjugated peptides derived from the known ACE2 inhibitor DX600 were synthesized, with variable linker identity. Since DX600 bears 2 cystine residues, both linear and cyclic peptides were studied. An ACE2 inhibition assay was used to identify lead compounds, which were labeled with 68Ga to generate peptide radiotracers (68Ga-NOTA-PEP). The aminocaproate-derived radiotracer 68Ga-NOTA-PEP4 was subsequently studied in a humanized ACE2 (hACE2) transgenic model. Results: Cyclic DX-600-derived peptides had markedly lower half-maximal inhibitory concentrations than their linear counterparts. The 3 cyclic peptides with triglycine, aminocaproate, and polyethylene glycol linkers had calculated half-maximal inhibitory concentrations similar to or lower than the parent DX600 molecule. Peptides were readily labeled with 68Ga, and the biodistribution of 68Ga-NOTA-PEP4 was determined in an hACE2 transgenic murine cohort. Pharmacologic concentrations of coadministered NOTA-PEP (blocking) showed a significant reduction of 68Ga-NOTA-PEP4 signals in the heart, liver, lungs, and small intestine. Ex vivo hACE2 activity in these organs was confirmed as a correlate to invivo results. Conclusion: NOTA-conjugated cyclic peptides derived from the known ACE2 inhibitor DX600 retain their activity when N-conjugated for 68Ga chelation. In vivo studies in a transgenic hACE2 murine model using the lead tracer, 68Ga-NOTA-PEP4, showed specific binding in the heart, liver, lungs and intestine-organs known to be affected in SARS-CoV-2 infection. These results suggest that 68Ga-NOTA-PEP4 could be used to detect organ-specific suppression of ACE2 in SARS-CoV-2-infected murine models and COVID-19 patients.
Highlights
The novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has had profound effects on global health, especially in the United States, the country with the largest number of confirmed coronavirus disease 2019 (COVID-19) cases, and associated deaths
The novel coronavirus disease (COVID-19) has spread rapidly throughout the world with the highest number of confirmed cases and deaths in the United States. Both biochemical studies and published cryo-EM structures have shown that the spike protein (S-protein) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) predominantly uses human angiotensin-converting enzyme 2 (ACE2) for viral entry, resulting in suppression of this enzyme as seen in SARS-CoV[25,46]
Additional recent publications have highlighted the possibility that the lower ACE2 activity seen with SARSCoV-2 infection may be responsible for the physiologic effects incurred, analogous to what was seen with the original SARS-CoV[25]
Summary
2) has had profound effects on global health, especially in the United States, the country with the largest number of confirmed coronavirus disease 2019 (COVID-19) cases, and associated deaths Many of these patients progress to Acute Respiratory Distress Syndrome (ARDS), respiratory failure with widespread injury of the lungs. Many pathologic conditions can cause this convergent picture, including both bacterial and viral infections These causes of ARDS likely share dysfunction of the renin-angiotensin system, especially loss of angiotensin converting enzyme II (ACE2) function[4,5,6,7,8]. ACE2 performs an important regulatory role, converting angiotensin II to angiotensin 1,7 which causes vasodilatation and has anti-inflammatory effect, unlike activation of ANGIOTENSIN RECEPTOR which will lead to vasoconstriction, higher blood pressure and inflammation (potentially ARDS)(10–13)
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