Carbosilane dendrons with fatty acids at the core as a new potential microbicide against HSV-2/HIV-1 co-infection

Abstract

Herpes simplex virus type 2 (HSV-2) and human immunodeficiency virus type 1 (HIV-1) represent the two most frequent sexually transmitted infections (STI) worldwide. Epidemiological studies suggest that HSV-2 increases the risk of HIV-1 acquisition approximately 3-fold mainly due to the clinical and immunological manifestations. In the absence of vaccines against both STI, the development of new preventive strategies has become essential for further studies. We performed the screening of six novel polyanionic carbosilane dendrons to elucidate their potential activity against HSV-2/HIV-1 co-infection and their mechanism of action. These new nanoparticles are carbosilane branched dendrons from first to third generation, with palmitic or hexanoic fatty acids as the core and capped with sulfonate groups, named G1-STE2Hx, G2-STE4Hx, G3-STE8Hx, G1-STE2Pm, G2-STE4Pm and G3-STE8Pm. G3-STE8Hx and G3-STE8Pm carbosilane branched dendrons showed high viability. These dendrons also showed a great broad-spectrum antiviral activity, as well as a suitable efficacy against HIV-1 even if the mucosal disruption occurs as a consequence of HSV-2 infection. Our results exert high inhibition against HSV-2 and HIV-1 by blocking the entry of both viruses with the median effective concentration EC values in the nanomolar range. Additionally, G3-STE8Hx and G3-STE8Pm retained their anti-HSV-2/HIV-1 activity at different pH values. G3-STE8Hx and G3-STE8Pm dendrons may be potential candidates as dual-acting microbicides against HSV-2/HIV-1 co-infection.

Baseline and time‐updated factors in preclinical development of anionic dendrimers as successful anti‐HIV‐1 vaginal microbicides

“…(Petrova et al, 2013). It is also essential to evaluate API's ability to inhibit other STIs, such as HIV‐2, HSV‐2, HPV, hepatitis viruses, and other pathogens associated with vaginosis or candidiasis (chlamydia, gonorrhea, or syphilis; Briz et al, 2015; Cena‐Diez, Vacas‐Cordoba, et al, 2016; Guerrero‐Beltran et al, 2017; Sepulveda‐Crespo, Jimenez, et al, 2017; Telwatte et al, 2011).…”

Dendrimers and Dendritic Materials: From Laboratory to Medical Practice in Infectious Diseases

“…Besides their own antiviral activity, Muñoz-Fernández et al showed that their combination with Tenofovir and Maraviroc (two antiviral agents) produce almost complete inhibition of HIV infection and transmission [ 80 ]. Carbosilane dendrimers are also efficient towards HIV-HSV coinfection [ 81 ] and can be employed in the development of fast diagnostic assays based on dendronized magnetic nanoparticles [ 82 ] tools. Dendrimers can also contribute to the design of efficient vaccines against HIV, such as the PEG-citrate G2 dendrimer bearing multiple HIV epitopes which produced a significant cellular immune response in vivo and a higher Th1 response compared to Th2 [ 83 ].…”

Emergence of Nanotechnology to Fight HIV Sexual Transmission: The Trip of G2-S16 Polyanionic Carbosilane Dendrimer to Possible Pre-Clinical Trials

“…No mortality or sign of vaginal discharge, erythema, edema, irritation, or inflammation at the lowest dose (5 mM) or a higher dose (50 mM) of G2-S16 PCD were detected. No characteristic abnormalities were found during the histopathological analysis of vaginal tissues, compared to the negative control [53,67,99,114]. Moreover, G2-S16 PCD was intravaginally applied for 7 consecutive days in BALB/c mice, at different doses and concentrations, based on the available literature [115], and pathological examinations of vaginal tissues were performed.…”