Inhibition of Herpes Simplex Virus-1 Entry into Human Cells by Nonsaccharide Glycosaminoglycan Mimetics

Gangji, Rahaman Navaz; Sankaranarayanan, Nehru Viji; Elste, James; Al‐Horani, Rami A.; Afosah, Daniel K.; Joshi, Rachel; Tiwari, Vaibhav; Desai, Umesh R.

doi:10.1021/acsmedchemlett.7b00364

Cited by 25 publications

(34 citation statements)

References 46 publications

(130 reference statements)

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“…This is especially important because Our study is first to report a unique heparin mimetic, which has been previously been reported as a broad spectrum antimicrobial activity, as an inhibitor of HCMV. Earlier, we have demonstrated that SPGG inhibits HSV [50,51] and Chlamydia infection [66]. Since HSV and Chlamydia are known to exploit heparan sulfate during early stages of host pathogen interactions [66,67], SPGG's lowering of HCMV early gene expression is not too surprising considering that the viral entry is blocked in the first place.…”

Section: The Impact Of Spgg Treatment On Hcmv Spreadmentioning

confidence: 92%

“…Another possibility is that SPGG mediates HCMV inhibition through multiple viral surface receptors, one of which is gB. The foundation for this expectation is that SPGG has been earlier shown to bind tightly to glycoprotein D of HSV [50,51]. Likewise, SPGG also inhibits Chlamydia infection through binding to its cell surface receptors [66].…”

Section: Spgg Inhibition Of Hcmv Entry Arises Partially From Binding mentioning

confidence: 99%

“…Cellular toxicity of SPGG (0.39100 µM) was evaluated after 24 h using lactate dehydrogenase (LDH) release as an indicator of damage to the plasma membrane. The assay was performed by using a cytotoxicity assay kit (Thermo Fisher, Waltham, MA, USA) as previously described [50].…”

Section: Ldh Cytotoxicity Assaymentioning

confidence: 99%

“…For some time now, we have been pursuing non-polymeric, non-saccharide mimetics of heparin/heparan sulfate as anti-viral [50][51][52][53][54], anti-cancer [55,56], and anti-thrombotic agents [57,58]. The advantage with these mimetics is that these are fully synthetic, easily characterizable, and highly amenable to advanced rational drug design possibilities.…”

Section: Introductionmentioning

confidence: 99%

“…The unique aspect of SPGG is its globular structure that theoretically can interact with diverse HS-binding proteins. In fact, our earlier work on SPGG has shown that it interacts with coagulation factor XIa [57,61] and glycoprotein gD [50], two completely different HS-binding proteins. Thus, we reasoned that the probability of targeting multiple proteins involved in cellular entry of HCMV, e.g., glycoprotein gB, PDGF-R, EGF-R, and neuropilin, would be higher with SPGG than with other non-saccharide mimetics developed so far.…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of Human Cytomegalovirus Entry into Host Cells through A Pleiotropic Small Molecule

Elste

Kaltenbach

Patel

et al. 2020

IJMS

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Human cytomegalovirus (HCMV) infections are wide-spread among the general population with manifestations ranging from asymptomatic to severe developmental disabilities in newborns and life-threatening illnesses in individuals with a compromised immune system. Nearly all current drugs suffer from one or more limitations, which emphasizes the critical need to develop new approaches and new molecules. We reasoned that a 'poly-pharmacy' approach relying on simultaneous binding to multiple receptors involved in HCMV entry into host cells could pave the way to a more effective therapeutic outcome. This work presents the study of a synthetic, small molecule displaying pleiotropicity of interactions as a competitive antagonist of viral or cell surface receptors including heparan sulfate proteoglycans and heparan sulfate-binding proteins, which play important roles in HCMV entry and spread. Sulfated pentagalloylglucoside (SPGG), a functional mimetic of heparan sulfate, inhibits HCMV entry into human foreskin fibroblasts and neuroepithelioma cells with high potency. At the same time, SPGG exhibits no toxicity at levels as high as 50-fold more than its inhibition potency. Interestingly, cell-ELISA assays showed downregulation in HCMV immediate-early gene 1 and 2 (IE 1&2) expression in presence of SPGG further supporting inhibition of viral entry. Finally, HCMV foci were observed to decrease significantly in the presence of SPGG suggesting impact on viral spread too. Overall, this work offers the first evidence that pleiotropicity, such as demonstrated by SPGG, may offer a new poly-therapeutic approach toward effective inhibition of HCMV.

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Section: The Impact Of Spgg Treatment On Hcmv Spreadmentioning

confidence: 92%

Section: Spgg Inhibition Of Hcmv Entry Arises Partially From Binding mentioning

confidence: 99%

Section: Ldh Cytotoxicity Assaymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Inhibition of Human Cytomegalovirus Entry into Host Cells through A Pleiotropic Small Molecule

Elste

Kaltenbach

Patel

et al. 2020

IJMS

Self Cite

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Anti‐DNA Virus Agents

Herdewijn¹,

Gu²,

Clercq³

2021

Burger's Medicinal Chemistry and Drug Discovery

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Although most of the drugs that are used to treat deoxyribonucleic acid (DNA) virus infections have been on the market for more than 10 years, anti‐DNA virus drug discovery remains an active field of research. There are still DNA viruses that are important human pathogens for which no therapy is available (i.e. adenovirus), for which the available drugs show considerable toxicity (i.e. cytomegalovirus), or for which the current drug therapy is insufficient to eradicate the virus (i.e. hepatitis B virus). In this article, we have provided an overview of the anti‐DNA virus drugs that are presently on the market together with a description of the new compounds, all active against DNA viruses, covering the literature of the past 10 years. We have focused on the structure of newly discovered compounds, and the mechanism of action and clinical data, when available. Although the major efforts are still in the nucleotide antimetabolite field, the anti‐DNA virus field of research and development has shifted recently in the direction of the study of more common heterocyclic structures as protein inhibitors.

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Nanoparticles-Mediated Interventions to Prevent Herpes Simplex Virus (HSV) Entry into Susceptible Hosts

Beer

Majmudar

Mishra

et al. 2021

Nanotechnology in the Life Sciences

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Inhibition of Herpes Simplex Virus-1 Entry into Human Cells by Nonsaccharide Glycosaminoglycan Mimetics

Cited by 25 publications

References 46 publications

Inhibition of Human Cytomegalovirus Entry into Host Cells through A Pleiotropic Small Molecule

Inhibition of Human Cytomegalovirus Entry into Host Cells through A Pleiotropic Small Molecule

Anti‐DNA Virus Agents

Nanoparticles-Mediated Interventions to Prevent Herpes Simplex Virus (HSV) Entry into Susceptible Hosts

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