Combination of Recombinant Bacterial ACE2 Receptors -Like Enzyme of B38-CAP and Isotretinoin Could be Promising Treatment for COVID-19 Infection- and Its Inflammatory Complications
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|ClinicalTrials.gov Identifier: NCT04382950|
Recruitment Status : Not yet recruiting
First Posted : May 11, 2020
Last Update Posted : June 9, 2021
Combination of Recombinant Bacterial ACE2 receptors -like enzyme of B38-CAP and Isotretinoin could be promising treatment for COVID-19 infection- and Its inflammatory complications
1Department of chemistry and biochemistry, Faculty of Science, Damietta University, Egypt.
B38-CAP is a bacteria-derived ACE2-like enzyme that suppresses hypertension and cardiac dysfunction Angiotensin-converting enzyme 2 (ACE2) is critically involved in cardiovascular physiology and pathology, and is currently clinically evaluated to treat acute lung failure. Here we show that the B38-CAP, a carboxypeptidase derived from Paenibacillus sp. B38, is an ACE2-like enzyme to decrease angiotensin II levels in mice. In protein 3D structure analysis, B38-CAP homolog shares structural similarity to mammalian ACE2 with low sequence identity. A study demonstrated that the bacterial B38-CAP as an ACE2-like carboxypeptidase, indicating that evolution has shaped a bacterial carboxypeptidase to a human ACE2-like enzyme. Bacterial engineering could be utilized to design improved protein drugs for hypertension and heart failure. pretreatment of B38-CAP markedly down regulated a massive increase of plasma Ang II levels at 5 min after Ang II injection In addition to the currently used drugs to inhibit Ang II generation or signaling, such as ACE inhibitors or Angiotensin receptor blockers, direct down-modulation of Ang II levels by rhACE2 protein is one of the promising candidates for new therapeutic strategy in cardiovascular disease and other Ang II-related diseases, e.g. ARDS. On the other hand, although mass production of rhACE2 as a protein drug costs due to requirement of mammalian cell expression systems, B38-CAP is easily prepared with E. coli expression system and is cost effective. Therapeutic efficacy and less toxicity in mouse heart failure models would warrant further investigation of B38-CAP or other microbial carboxypeptidases in disease models. Finally the principal investigator expects that treatment with ACE2-like enzyme of bacteria B38-CAP expected to work efficiently Like human ACE2 and it will save the lung cells from COVID - 19 inhibitory effect and down regulation of ACE2 because COVID-19 binds to human ACE2 and down regulates it and this receptors is very important for lung cells survival and function So ,the principal investigator also expects that B38-CAP ACE2 like enzyme may be not recognized by COVID -19 spike protein because evolutionary it is too far away from human ace2 and human ACE2 is a real receptor of COVID -19 not ACE2 like enzyme but in the same time it will make the same function of human ACE2 In another study by Sinha et al who analyzed a publicly available Connectivity Map (CMAP) dataset of pre/post transcriptomic profiles for drug treatment in cell lines for over 20,000 small molecules, isotretinoin was the strongest down-regulator of ACE 2 receptors. On the other hand, they found 6 drugs in CMAP that are currently being investigated in clinical trials for treating COVID-19 (chloroquine, thalidomide, methylprednisolone, losartan, lopinavir and ritonavir, from clinicaltrials.gov), none of which was found to significantly alter ACE2 expression (P>0.1) Moreover, another study demonstrated that isotretinoin is a Potential papain like protease (PLpro) inhibitors which is a protein encoded by SARS-CoV-2 genes and considered one of the proteins that should be targeted in COVID-19 treatment by performing target-based virtual ligand screening . So, the principal investigator expects strong inhibition of COVID - 19 infection And rescuing the lung cells from its serious attack by treating with ACE2 like enzyme and Isotretinoin
Keywords: COVID 2019 , Isotretinoin,B38-CAP , Bacterial ACE2 receptors -like enzyme , rhACE226.
|Condition or disease||Intervention/treatment||Phase|
|COVID||Combination Product: Recombinant Bacterial ACE2 receptors -like enzyme of B38-CAP (rbACE2) plus Aerosolized 13 cis retinoic acid||Phase 1|
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||24 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||None (Open Label)|
|Official Title:||Combination of Recombinant Bacterial ACE2 Receptors -Like Enzyme of B38-CAP and Isotretinoin Could be Promising Treatment for COVID-19 Infection- and Its Inflammatory Complications|
|Estimated Study Start Date :||July 2021|
|Estimated Primary Completion Date :||August 2021|
|Estimated Study Completion Date :||October 2021|
Experimental: Experimental: rbACE2 group plus Aerosolized Isotretinoin
rbACE2 0.4 mg/kg IV BID for 7 days (unblinded) plus Aerosolized 13 cis retinoic acid in gradual in 2 divided doses increases froms 0.2 mg/kg/day to 4 mg/kg/day as inhaled 13 cis retinoic acid therapy for 14 days
Combination Product: Recombinant Bacterial ACE2 receptors -like enzyme of B38-CAP (rbACE2) plus Aerosolized 13 cis retinoic acid
In this study, the experimental group will receive 0.4 mg/kg rbACE2 IV plus Aerosolized 13 cis retinoic acid in gradual in 2 divided doses increases froms 0.2 mg/kg/day to 4 mg/kg/day as inhaled 13 cis retinoic acid therapy for 14 days
No Intervention: No Intervention: Control group
Standard of care; no placebo
- Time course of body temperature (fever) [ Time Frame: at 14 days ]Compare the time course of body temperature (fever) between two groups over time.
- Viral load over time [ Time Frame: 14 days ]Compare viral load between two groups over time.
- P/F ratio over time [ Time Frame: 14 days ]PaO2/FiO2 ratio
- Sequential organ failure assessment score(SOFA score) over time [ Time Frame: 14 days ]SOFA, including assessment of respiratory, blood, liver, circulatory, nerve, kidney, from 0 to 4 scores in each systems, the higher scores mean a worse outcome.
- Pulmonary Severity Index (PSI) [ Time Frame: 14 days ]
- Image examination of chest over time [ Time Frame: 14 days ]Based on radiologist's assessment of inflammatory exudative disease, category as follows: significant improvement, partial improvement, no improvement, increase of partial exudation, significant increase in exudation, unable to judge.
- Proportion of subjects who progressed to critical illness or death [ Time Frame: at 14 days ]
- Time from first dose to conversion to normal or mild pneumonia [ Time Frame: 14 days ]
- T-lymphocyte counts over time [ Time Frame: 14 days ]
- C-reactive protein levels over time [ Time Frame: 14 days ]
- Angiotensin II (Ang II) changes over time [ Time Frame: 14 days ]
- Angiotensin 1-7 (Ang 1-7) changes over time [ Time Frame: 14 days ]
- Angiotensin 1-5 (Ang 1-5) changes over time [ Time Frame: 14 days ]
- Renin changes over time [ Time Frame: 14 days ]
- Aldosterone changes over time [ Time Frame: 14 days ]
- Angiotensin-converting enzyme (ACE) changes over time [ Time Frame: 14 days ]
- Interleukin 6 (IL-6) changes over time [ Time Frame: 14 days ]
- Soluble tumor necrosis factor receptor type II (sTNFrII) changes over time [ Time Frame: 14 days ]
- Plasminogen activator inhibitor type-1 (PAI-1) changes over time [ Time Frame: 14 days ]
- Von willebrand factor (vWF) changes over time [ Time Frame: 14 days ]
- Tumor necrosis factor-α (TNF-α) changes over time [ Time Frame: 14 days ]
- Soluble receptor for advanced glycation end products (sRAGE) changes over time [ Time Frame: 14 days ]
- Surfactant protein-D (SP-D) changes over time [ Time Frame: 14 days ]
- Frequency of adverse events and severe adverse events [ Time Frame: 14 days ]
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04382950
|Contact: M.Sc.Mahmoud Elkazzaz, M.Sc.Biochemistryfirstname.lastname@example.org|
|Principal Investigator:||M.Sc. Mahmoud Elkazzaz, M.Sc.Biochemistry||General Organization of Export and Import control system|