Human ACE2 peptide mimics block SARS-CoV-2 Pulmonary Cells Infection

Karoyan, Philippe; Vieillard, Vincent; Odile, Estelle; Denis, Alexis; Guihot, Amélie; Luyt, Charles‐Édouard; Gómez‐Morales, Luis; Grondin, Pascal; Lequin, Olivier

doi:10.1101/2020.08.24.264077

Cited by 21 publications

(25 citation statements)

References 32 publications

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“…Recombinant soluble human ACE2 fused to the Fc region of the human immunoglobulin IgG1 to increase short half-life of soluble ACE2 ( Iwanaga et al, 2020 ; Lei et al, 2020 ) and human recombinant soluble ACE2 ( Monteil et al, 2020 ) have been shown to inhibit SARS-CoV-2 infection in cell lines, engineered human blood vessels and kidney organoids. Recently, peptides mimicking the N-terminal helix of the human ACE2 protein, which contains most of the contacting residues for the S protein-binding site, were shown to block infection of human pulmonary cells with SARS-CoV-2, with IC 50 values in the range of 60-800 nM ( Karoyan et al, 2020 ). Similarly, ACE2 peptides optimized to SARS-CoV-2 spike protein binding regions using protein-engineering methods potently bound to the spike protein with a 170-fold higher affinity than wild-type ACE2 and inhibited SARS-CoV-2 infection (IC 50 of 28 ng/ml) in cell lines ( Glasgow et al, 2020 ).…”

Section: Antiviral Agents and Other Drugs On Ace2mentioning

confidence: 99%

A comprehensive guide to the pharmacologic regulation of angiotensin converting enzyme 2 (ACE2), the SARS-CoV-2 entry receptor

Öz

Lorke

Kabbani

2021

Pharmacology & Therapeutics

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The recent emergence of coronavirus disease-2019 (COVID-19) as a global pandemic has prompted scientists to address an urgent need for defining mechanisms of disease pathology and treatment. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent for COVID-19, employs angiotensin converting enzyme 2 (ACE2) as its primary target for cell surface attachment and likely entry into the host cell. Thus, understanding factors that may regulate the expression and function of ACE2 in the healthy and diseased body is critical for clinical intervention. Over 66% of all adults in the United States are currently using a prescription drug and while earlier findings have focused on possible upregulation of ACE2 expression through the use of renin angiotensin system (RAS) inhibitors, mounting evidence suggests that various other widely administered drugs used in the treatment of hypertension, heart failure, diabetes mellitus, hyperlipidemias, coagulation disorders, and pulmonary disease may also present a varied risk for COVID-19. Specifically, we summarize mechanisms on how heparin, statins, steroids and phytochemicals, besides their established therapeutic effects, may also interfere with SARS-CoV-2 viral entry into cells. We also describe evidence on the effect of several vitamins, phytochemicals, and naturally occurring compounds on ACE2 expression and activity in various tissues and disease models. This comprehensive review aims to provide a timely compendium on the potential impact of commonly prescribed drugs and pharmacologically active compounds on COVID-19 pathology and risk through regulation of ACE2 and RAS signaling.

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Section: Antiviral Agents and Other Drugs On Ace2mentioning

confidence: 99%

A comprehensive guide to the pharmacologic regulation of angiotensin converting enzyme 2 (ACE2), the SARS-CoV-2 entry receptor

Öz

Lorke

Kabbani

2021

Pharmacology & Therapeutics

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“…Another study used a programmatic approach to search and identification based on the hACE2 sequence of ten peptides that have a high potential for interaction with CoV-RBD [ 250 ]. Drugs targeting this mechanism are not yet available, but the recent work has demonstrated that peptide hACE2 mimics, creating from the H1 helix and consisting only of natural amino acids, block infection of human lung cells with IC50 in the nM range [ 251 ]. It is about eliminating the effect on the renin–angiotensin system and the kinin–kallikrein system in the light of the pathophysiological mechanisms associated with SARS-CoV-2 [ 252 , 253 ].…”

Section: Prediction and Development Of New Ampsmentioning

confidence: 99%

Antimicrobial and Amyloidogenic Activity of Peptides. Can Antimicrobial Peptides Be Used against SARS-CoV-2?

Kurpe

Grishin

Surin

et al. 2020

IJMS

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At present, much attention is paid to the use of antimicrobial peptides (AMPs) of natural and artificial origin to combat pathogens. AMPs have several points that determine their biological activity. We analyzed the structural properties of AMPs, as well as described their mechanism of action and impact on pathogenic bacteria and viruses. Recently published data on the development of new AMP drugs based on a combination of molecular design and genetic engineering approaches are presented. In this article, we have focused on information on the amyloidogenic properties of AMP. This review examines AMP development strategies from the perspective of the current high prevalence of antibiotic-resistant bacteria, and the potential prospects and challenges of using AMPs against infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

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“…57, 58, 59 Due to their unique physico-chemical properties (hydrophobicity, cationic charge) enabling impact to viruses prior to infection, HDPs are well-suited for prophylactic development, as some HDPs appear to behave in a manner similar to the neutralization of virus observed in the presence of neutralizing antibodies. 60, 61, 62, 63 Numerous recently published reports 64, 65, 66, 67, 68, 69, 70, 71, 72 support the antiviral activity of HDPs in the context of coronaviruses, 73 including SARS-CoV-2.…”

Section: Introductionmentioning

confidence: 90%

Brilacidin, a COVID-19 Drug Candidate, Exhibits PotentIn VitroAntiviral Activity Against SARS-CoV-2

Bakovic

Risner

Bhalla

et al. 2020

Preprint

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Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the newly emergent causative agent of coronavirus disease-19 (COVID-19), has resulted in more than one million deaths worldwide since it was first detected in 2019. There is a critical global need for therapeutic intervention strategies that can be deployed to safely treat COVID-19 disease and reduce associated morbidity and mortality. Increasing evidence shows that both natural and synthetic antimicrobial peptides (AMPs), also referred to as Host Defense Proteins/Peptides (HDPs), can inhibit SARS-CoV-2, paving the way for the potential clinical use of these molecules as therapeutic options. In this manuscript, we describe the potent antiviral activity exerted by brilacidin−a de novo designed synthetic small molecule that captures the biological properties of HDPs−on SARS-CoV-2 in a human lung cell line (Calu-3) and a monkey cell line (Vero). These data suggest that SARS-CoV-2 inhibition in these cell culture models is primarily a result of the impact of brilacidin on viral entry and its disruption of viral integrity. Brilacidin has demonstrated synergistic antiviral activity when combined with remdesivir. Collectively, our data demonstrate that brilacidin exerts potent inhibition of SARS-CoV-2 and thus supports brilacidin as a promising COVID-19 drug candidate. Highlights: Brilacidin potently inhibits SARS-CoV-2 in an ACE2 positive human lung cell line. Brilacidin achieved a high Selectivity Index of 426 (CC50=241µM/IC50=0.565µM). Brilacidin's main mechanism appears to disrupt viral integrity and impact viral entry. Brilacidin and remdesivir exhibit excellent synergistic activity against SARS-CoV-2. Significance Statement: SARS-CoV-2, the emergent novel coronavirus, has led to the current global COVID-19 pandemic, characterized by extreme contagiousness and high mortality rates. There is an urgent need for effective therapeutic strategies to safely and effectively treat SARS-CoV-2 infection. We demonstrate that brilacidin, a synthetic small molecule with peptide-like properties, is capable of exerting potent in vitro antiviral activity against SARS-CoV-2, both as a standalone treatment and in combination with remdesivir, which is currently the only FDA-approved drug for the treatment of COVID-19.

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Human ACE2 peptide mimics block SARS-CoV-2 Pulmonary Cells Infection

Cited by 21 publications

References 32 publications

A comprehensive guide to the pharmacologic regulation of angiotensin converting enzyme 2 (ACE2), the SARS-CoV-2 entry receptor

A comprehensive guide to the pharmacologic regulation of angiotensin converting enzyme 2 (ACE2), the SARS-CoV-2 entry receptor

Antimicrobial and Amyloidogenic Activity of Peptides. Can Antimicrobial Peptides Be Used against SARS-CoV-2?

Brilacidin, a COVID-19 Drug Candidate, Exhibits PotentIn VitroAntiviral Activity Against SARS-CoV-2

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