Elucidation of the mechanism of anti-herpes action of two novel semisynthetic cardenolide derivatives

Abstract

Human herpesviruses are among the most prevalent pathogens worldwide and have become an important public health issue. Recurrent infections and the emergence of resistant viral strains reinforce the need of searching new drugs to treat herpes virus infections. Cardiac glycosides are used clinically to treat cardiovascular disturbances, such as congestive heart failure and atrial arrhythmias. In recent years, they have sparked new interest in their potential anti-herpes action. It has been previously reported by our research group that two new semisynthetic cardenolides, namely C10 (3β-[(N-(2-hydroxyethyl)aminoacetyl] amino-3-deoxydigitoxigenin) and C11 (3β-(hydroxyacetyl)amino-3-deoxydigitoxigenin), exhibited potential anti-HSV-1 and anti-HSV-2 with selectivity index values > 1,000, comparable with those of acyclovir. This work reports the mechanism investigation of anti-herpes action of these derivatives. The results demonstrated that C10 and C11 interfere with the intermediate and final steps of HSV replication, but not with the early stages, since they completely abolished the expression of the UL42 (β) and gD (γ) proteins and partially reduced that of ICP27 (α). Additionally, they were not virucidal and had no prophylactic effects. Both compounds inhibited HSV replication at nanomolar concentrations, but cardenolide C10 was more active than C11 and can be considered as an anti-herpes drug candidate including against acyclovir-resistant HSV-1 strains. AbbreviationsACV acyclovir CC 50 50% cytotoxic concentration CMC carboxymethylcellulose DEX-S dextran sulfate FBS fetal bovine serum HIV human immunodeficiency virus HSV-1 herpes simplex virus type 1 HSV-2 herpes simplex virus type 2 HPV human papillomavirus IC 50 concentration that inhibited 50% of viral replication MEM Eagle's minimum essential medium MOI multiplicity of infection PBS phosphate-buffered saline PFU plaque-forming units SI selectivity index

Semisynthetic Cardenolides Acting as Antiviral Inhibitors of Influenza A Virus Replication by Preventing Polymerase Complex Formation

“…Cardenolides are molecules clinically used to treat heart diseases, such as heart failure, arrhythmias, and cardiogenic shock [ 25 , 26 , 27 ]. However, several studies have suggested promising effects for the treatment of other diseases [ 54 ], including those caused by viral infections [ 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 ]. Even though CGs have been investigated against many viruses, little is known about their potential anti-influenza activity.…”

“…In recent years, these compounds have been investigated for the treatment of other pathological conditions, such as viral infections. Their potential antiviral activity against a wide variety of viruses has been reported, such as adenovirus [ 29 ], chikungunya virus [ 30 ], coronavirus [ 31 , 32 , 33 ], cytomegalovirus [ 34 , 35 , 36 ], dengue virus [ 37 ], herpes virus [ 38 , 39 , 40 , 41 ], HIV [ 42 , 43 , 44 ], human papillomavirus [ 45 ], influenza virus [ 46 , 47 , 48 ], and respiratory syncytial virus [ 49 ].…”

“…Furthermore, the cytotoxic effects of some derivatives on H460 lung cancer cells were deeply investigated using different methodological approaches [ 51 ]. We also reported a proposal for the mechanism of anti-herpes action of C10 and C11 , which interfered with the intermediate and final steps of HSV replication, but not with the early stages since they completely abolished the expression of the UL42 (β) and gD (γ) proteins and partially reduced that of ICP27 (α); additionally, they were not virucidal and had no prophylactic effects [ 41 ].…”

(E)-N-(3,4-dimethylisoxazol-5-yl)-4-((4-hydroxy-2-oxo-2H-chromen-3-yl) diazenyl)Benzenesulfonamide; A New Synthetic Anti-Herpetic Agent for HSV-1

“…To explore the attribute of HDF to intrupt protein expression of HSV-1, western blotting technique was employed. 24,25) Vero cells, previously washed with phosphate buffer saline centrifuged for 15 minutes and pellets were adjourned in cold lymph buffer solution containing 10mM phenyl methacophenol fluoride phosphatase as inhibitor mixture along with 2% triton solution, incubated for 30 minutes at 0°C temperature and supernatants were arrassed to negotiate protein expression. The protein contents were aloofed by gel electrophoresis technique in 10% S.D.S.…”

<p>Antiviral Effects of Oleandrin</p>

“…They also presented data demonstrating that this cardiac glycoside was effective against acyclovir-resistant viruses. Recently, Boff et al 78 published their experience with several semisynthetic cardenolides, C10 (3β-[(N-(2-hydroxyethyl) aminoacetyl]amino-3-deoxydigitoxigenin)) and C11 (3β-(hydroxyacetyl) amino-3-deoxydigitoxigenin), both of which inhibited HSV-1 and HSV-2 at nM concentrations. Both compounds inhibited the intermediate and final steps of HSV replication, but not the earlier stages, based on the complete reduction in the expression of UL42 (β) and gD (γ) proteins and partial reduction of ICP27 (α).…”