Abstract
Infections caused by viruses from the Herpesviridae family produce some of the most prevalent transmitted diseases in the world, constituting a serious global public health issue. Some of the virus properties such as latency and the appearance of resistance to antiviral treatments complicate the development of effective therapies capable of facing the infection. In this context, dendrimers present themselves as promising alternatives to current treatments. In this study, we propose the use of PEGylated cationic carbosilane dendrimers as inhibitors of herpes simplex virus 2 (HSV-2) and human cytomegalovirus (HCMV)infections. Studies of mitochondrial toxicity, membrane integrity, internalization and viral infection inhibition indicated that G2-SN15-PEG, G3-SN31-PEG, G2-SN15-PEG fluorescein isothiocyanate (FITC) labeled and G3-SN31-PEG-FITC dendrimers are valid candidates to target HSV-2 and HCMV infections since they are biocompatible, can be effectively internalized and are able to significantly inhibit both infections. Later studies (including viral inactivation, binding inhibition, heparan sulphate proteoglycans (HSPG)binding and surface plasmon resonance assays) confirmed that inhibition takes place at first infection stages. More precisely, these studies established that their attachment to cell membrane heparan sulphate proteoglycans impede the interaction between viral glycoproteins and these cell receptors, thus preventing infection. Altogether, our research confirmed the high capacity of these PEGylated carbosilane dendrimers to prevent HSV-2 and HCMV infections, making them valid candidates as antiviral agents against Herpesviridae infections.
Highlights
Herpesviridae is a large family of enveloped double-stranded DNA viruses that comprises a wide variety of herpesviruses with different biological characteristics, but that have in common basic properties such as their ability to infect animals, their morphology, their genetic complexity and a high regulated transcription [1].The International Committee on Taxonomy of Viruses (ICTV) established the division of this family in three subfamilies: (i) Alfaherpesviridae, (ii) Gammaherpesviridae, and (iii) Betaherpesviridae [2]
We present the use of four PEGylated cationic carbosilane dendrimers (PCCDs), G2-SN15-polyethylene glycol (PEG), G3-SN31-PEG, G2-SN15-PEG-fluorescein isothiocyanate (FITC) and G3-SN31-PEG-FITC, which are characterized by the presence of positively charged functional terminal groups and PEGylation residues [26]
Results obtained from the MTT assay (Figure 1A,B) were more restrictive than those obtained from the lactate dehydrogenase (LDH) assay (Figure 1C,D), we considered those results for the obtained from the LDH assay (Figure 1C,D), we considered those results for the determination of the working concentrations
Summary
The International Committee on Taxonomy of Viruses (ICTV) established the division of this family in three subfamilies: (i) Alfaherpesviridae, (ii) Gammaherpesviridae, and (iii) Betaherpesviridae [2] They are divided into different subtypes, including herpes simplex. Pharmaceutics 2022, 14, 536 virus 1 and 2 (HSV-1 and HSV-2), Epstein–Barr virus (EBV), varicella zoster virus (VZV), or human cytomegalovirus (HCMV). Those are among the most widespread pathogens in the word; more than 90% of adults have been infected with one of these subtypes [3,4]. One of the most prevalent infections is the one produced by HSV-2 which, according with the latest available data, affects nearly 500 million people, mainly women from Africa, aged between 15 to 49 years old [6]. HCMV is mainly asymptomatic but can lead to life-threatening diseases in immunocompromised individuals, producing manifestations such as mononucleosis-like syndrome, tissue-invasive disease, neutropenia, interstitial pneumonia or autoimmune phenomena (vasculitis, scleroderma, systemic lupus erythematosus, etc.) [9]
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