Repurposing the clinically approved calcium antagonist manidipine dihydrochloride as a new early inhibitor of human cytomegalovirus targeting the Immediate-Early 2 (IE2) protein

Mercorelli, Beatrice; Luganini, Anna; Celegato, Marta; Palù, Giorgio; Gribaudo, Giorgio

doi:10.1016/j.antiviral.2017.12.014

Cited by 22 publications

(16 citation statements)

References 38 publications

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“…This antiviral activity was observed for laboratory, clinical and drug-resistant HCMV isolates. Further, MND was shown to be inactive against a selection of other DNA and RNA viruses and is thus likely to be a specific anti-HCMV compound [381]. The antiviral mechanism of these compounds was confirmed to be inhibition of IE2-mediated viral early gene transactivation and, like with WC5, a minimal 150-bp segment of the UL54 promoter is sufficient for inhibitory activity.…”

Section: Ie2 Inhibitorsmentioning

confidence: 97%

“…Assay optimization identified conditions using the stable cell-line that expresses EGFP under the control of the IE2-dependent UL54 early promoter as suitable for screening purposes [364]. A 2320 bioactive compound library including all FDA-approved drugs was screened and six hit compounds have so far been selected for further study [364,381,382]. These hit compounds are deguelin (DGN), nitazoxanide (NTZ), thioguanosine (TGN), alexidine dihydrochloride (AXN), manidipine dihydrochloride (MND) and berberine (BBR).…”

Section: Ie2 Inhibitorsmentioning

confidence: 99%

“…However, the precise mechanism of action has not been elucidated, although prior knowledge of these bioactive compounds has led to the proposal that they are likely to interfere with pathways in HCMV-infected cells that are required for the switch from the IE to early phase of viral replication [364]. Despite the lack of a precise mechanism of action, repurposing of bioactive compounds for anti-HCMV activities may allow compound development to be fast-tracked, especially in the case of MND, as it is already an FDA-approved drug used in the treatment of hypertension [381].…”

Section: Ie2 Inhibitorsmentioning

confidence: 99%

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Bright and Early: Inhibiting Human Cytomegalovirus by Targeting Major Immediate-Early Gene Expression or Protein Function

Adamson

Nevels

2020

Viruses

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The human cytomegalovirus (HCMV), one of eight human herpesviruses, establishes lifelong latent infections in most people worldwide. Primary or reactivated HCMV infections cause severe disease in immunosuppressed patients and congenital defects in children. There is no vaccine for HCMV, and the currently approved antivirals come with major limitations. Most approved HCMV antivirals target late molecular processes in the viral replication cycle including DNA replication and packaging. “Bright and early” events in HCMV infection have not been exploited for systemic prevention or treatment of disease. Initiation of HCMV replication depends on transcription from the viral major immediate-early (IE) gene. Alternative transcripts produced from this gene give rise to the IE1 and IE2 families of viral proteins, which localize to the host cell nucleus. The IE1 and IE2 proteins are believed to control all subsequent early and late events in HCMV replication, including reactivation from latency, in part by antagonizing intrinsic and innate immune responses. Here we provide an update on the regulation of major IE gene expression and the functions of IE1 and IE2 proteins. We will relate this insight to experimental approaches that target IE gene expression or protein function via molecular gene silencing and editing or small chemical inhibitors.

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Section: Ie2 Inhibitorsmentioning

confidence: 97%

Section: Ie2 Inhibitorsmentioning

confidence: 99%

Section: Ie2 Inhibitorsmentioning

confidence: 99%

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Bright and Early: Inhibiting Human Cytomegalovirus by Targeting Major Immediate-Early Gene Expression or Protein Function

Adamson

Nevels

2020

Viruses

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“…In this context, different DR campaigns identified several approved or investigational drugs with an anti-HCMV mechanism different from that of the currently available drugs [62,63]. This is the case for statins [64], cardiac glycosides [65], the antiparasitic drugs emetine and nitazoxanide [62,66], kinase inhibitors [67], and the antihypertensive drug manidipine [68]. All of these drugs pharmacologically modulate host proteins; thus, although a specific viral target cannot be excluded, the anti-HCMV activity most likely relies on the interference with host pathways that are intercepted by the virus.…”

Section: Drug Repurposing For Dna Virus Infectionsmentioning

confidence: 99%

Drug Repurposing for Viral Infectious Diseases: How Far Are We?

Mercorelli

Palù

Loregian

2018

Trends in Microbiology

Self Cite

228

188

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Despite the recent advances in controlling some viral pathogens, most viral infections still lack specific treatment. Indeed, the need for effective therapeutic strategies to combat 'old', emergent, and re-emergent viruses is not paralleled by the approval of new antivirals. In the past years, drug repurposing combined with innovative approaches for drug validation, and with appropriate animal models, significantly contributed to the identification of new antiviral molecules and targets for therapeutic intervention. In this review, we describe the main strategies of drug repurposing in antiviral discovery, discuss the most promising candidates that could be repurposed to treat viral infections, and analyze the possible caveats of this trendy strategy of drug discovery.

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“…Results of screening drug libraries have revealed several other mammalian cell pathways that may be targeted. For example, blockers of Ca 2+ and other ion channels are reported to have in vitro activity against Ebola, Japanese Encephalitis virus, human cytomegalovirus and arenaviruses such as Lassa fever …”

Section: Finding New Uses For Approved Drugsmentioning

confidence: 99%

Repurposing approved drugs on the pathway to novel therapies

Schein

2019

Medicinal Research Reviews

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The time and cost of developing new drugs have led many groups to limit their search for therapeutics to compounds that have previously been approved for human use. Many “repurposed” drugs, such as derivatives of thalidomide, antibiotics, and antivirals have had clinical success in treatment areas well beyond their original approved use. These include applications in treating antibiotic‐resistant organisms, viruses, cancers and to prevent burn scarring. The major theoretical justification for reusing approved drugs is that they have known modes of action and controllable side effects. Coadministering antibiotics with inhibitors of bacterial toxins or enzymes that mediate multidrug resistance can greatly enhance their activity. Drugs that control host cell pathways, including inflammation, tumor necrosis factor, interferons, and autophagy, can reduce the “cytokine storm” response to injury, control infection, and aid in cancer therapy. An active compound, even if previously approved for human use, will be a poor clinical candidate if it lacks specificity for the new target, has poor solubility or can cause serious side effects. Synergistic combinations can reduce the dosages of the individual components to lower reactivity. Preclinical analysis should take into account that severely ill patients with comorbidities will be more sensitive to side effects than healthy trial subjects. Once an active, approved drug has been identified, collaboration with medicinal chemists can aid in finding derivatives with better physicochemical properties, specificity, and efficacy, to provide novel therapies for cancers, emerging and rare diseases.

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Repurposing the clinically approved calcium antagonist manidipine dihydrochloride as a new early inhibitor of human cytomegalovirus targeting the Immediate-Early 2 (IE2) protein

Cited by 22 publications

References 38 publications

Bright and Early: Inhibiting Human Cytomegalovirus by Targeting Major Immediate-Early Gene Expression or Protein Function

Bright and Early: Inhibiting Human Cytomegalovirus by Targeting Major Immediate-Early Gene Expression or Protein Function

Drug Repurposing for Viral Infectious Diseases: How Far Are We?

Repurposing approved drugs on the pathway to novel therapies

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