Potential Anti-COVID-19 Therapeutics that Block the Early Stage of the Viral Life Cycle: Structures, Mechanisms, and Clinical Trials

Al‐Horani, Rami A.; Kar, Srabani; Aliter, Kholoud F.

doi:10.3390/ijms21155224

Cited by 53 publications

(63 citation statements)

References 300 publications

(336 reference statements)

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“…In this manuscript, we demonstrate brilacidin exhibits robust inhibition of SARS-CoV-2 in Vero cells and Calu-3 cells, and in two strains of the virus. Likely to function as a viral entry inhibitor [ 73 , 74 , 75 ], the proposed mechanism of action for brilacidin includes affecting the integrity of the viral membrane and interfering with viral entry. Brilacidin also exhibited an excellent synergistic inhibitory profile against SARS-CoV-2 in combination with remdesivir.…”

Section: Discussionmentioning

confidence: 99%

Brilacidin Demonstrates Inhibition of SARS-CoV-2 in Cell Culture

Bakovic

Risner

Bhalla

et al. 2021

Viruses

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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 two 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 likely to be a result of the impact of brilacidin on viral entry and its disruption of viral integrity. Brilacidin demonstrated synergistic antiviral activity when combined with remdesivir. Collectively, our data demonstrate that brilacidin exerts potent inhibition of SARS-CoV-2 against different strains of the virus in cell culture.

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Section: Discussionmentioning

confidence: 99%

Brilacidin Demonstrates Inhibition of SARS-CoV-2 in Cell Culture

Bakovic

Risner

Bhalla

et al. 2021

Viruses

View full text Add to dashboard Cite

show abstract

“…In this manuscript, we demonstrate brilacidin exhibits robust inhibition of SARS-CoV-2 in Vero cells and Calu-3 cells, supporting brilacidin as a promising novel drug candidate for the treatment of COVID-19. Functioning as a viral entry inhibitor, 95, 96, 97 proposed mechanisms of action for brilacidin include affecting the integrity of the viral membrane and preventing viral binding to cells. More detailed mechanistic studies are planned.…”

Section: Discussionmentioning

confidence: 99%

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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“…Janus kinase inhibitors) or with virus replication (imatinib). Angiotensin converting enzyme inhibitors or angiotensin receptor blockers, hydroxy methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors and several other compounds have also been tested as single usage or in combination approaches (Lam et al, 2020, Al-Horani et al, 2020, Sharma et al, 2020, Santos et al, 2020), thus illustrating an increasing relevance of host-targeting antiviral therapeutic strategies to combat COVID-19.…”

Section: Discussionmentioning

confidence: 99%

The rocaglate CR-31-B (-) inhibits SARS-CoV-2 replication at non-cytotoxic, low nanomolar concentrationsin vitroandex vivo

Müller

Obermann

Karl

et al. 2020

Preprint

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a betacoronavirus in the subgenus Sarbecovirus causes a respiratory disease with varying symptoms referred to as coronavirus disease 2019 (COVID-19) and is responsible for a pandemic that started in early 2020. With no vaccines or effective antiviral treatments available, and infection and fatality numbers continuing to increase globally, the quest for novel therapeutic solutions remains an urgent priority. Rocaglates, a class of plant-derived cyclopenta[b]benzofurans, exhibit broad-spectrum antiviral activity against positive- and negative-sense RNA viruses. This compound class inhibits eukaryotic initiation factor 4A (eIF4A)-dependent mRNA translation initiation, resulting in strongly reduced viral RNA translation. The synthetic rocaglate CR-31-B (-) has previously been shown to inhibit the replication of human coronaviruses, such as HCoV-229E and MERS-CoV, as well as Zika-, Lassa-, Crimean Congo hemorrhagic fever virus in primary cells. Here, we assessed the antiviral activity of CR-31-B (-) against SARS-CoV-2 using both in vitro and ex vivo cell culture models. In African green monkey Vero E6 cells, CR-31-B (-) inhibited SARS-CoV-2 replication with an EC50 of ~1.8 nM. In line with this, viral protein accumulation and replication/transcription complex formation were found to be strongly reduced by this compound. In an ex vivo infection system using human airway epithelial cells, CR-31-B (-) was found to cause a massive reduction of SARS-CoV-2 titers by about 4 logs to nearly non-detectable levels. The data reveal a potent anti-SARS-CoV-2 activity by CR-31-B (-), corroborating previous results obtained for other coronaviruses and supporting the idea that rocaglates may be used in first-line antiviral intervention strategies against novel and emerging RNA virus outbreaks.

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Potential Anti-COVID-19 Therapeutics that Block the Early Stage of the Viral Life Cycle: Structures, Mechanisms, and Clinical Trials

Cited by 53 publications

References 300 publications

Brilacidin Demonstrates Inhibition of SARS-CoV-2 in Cell Culture

Brilacidin Demonstrates Inhibition of SARS-CoV-2 in Cell Culture

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

The rocaglate CR-31-B (-) inhibits SARS-CoV-2 replication at non-cytotoxic, low nanomolar concentrationsin vitroandex vivo

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