Effect of Several HIV Antigens Simultaneously Loaded with G2-NN16 Carbosilane Dendrimer in the Cell Uptake and Functionality of Human Dendritic Cells

Sepúlveda‐Crespo, Daniel; Vacas-Córdoba, Enrique; Márquez-Miranda, Valeria; Araya-Durán, Ingrid; Gómez, Rafael; Mata, F. Javier de la; González‐Nilo, Fernando; Muñoz‐Fernández, María Ángeles

doi:10.1021/acs.bioconjchem.6b00623

Cited by 8 publications

(6 citation statements)

References 26 publications

(36 reference statements)

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“…The same procedure was carried out for systems considering G2-S16 dendrimer. Then, the gp120-CD4 binding free energy, Δ G binding , was calculated using the Molecular Mechanics/Generalized Born surface area method (MM-GBSA) as previously reported, ,, considering the follow equation: where H MM contribution was calculated by summing the in vacuo gas-phase nonbond energies ( H MM = E vDW + E ele ) and the solvation free energies (( G sol ) = G GB + G NP ) for each component, e.g., gp120-CD4 complex, gp120 protein, and CD4 protein. Polar solvation free energy G GB was calculated using Generalized Born approach and nonpolar solvation G NP was calculated as γ (SASA) + β, in which γ = 0.00542 kcal/Å 2 and β = 0.92 kcal/mol .…”

Section: Methodsmentioning

confidence: 99%

“…G2-S16 dendrimer structure was built in full atomic detail, by splitting it into fragments: one core, two monomers, and one terminal group, as described in a previous work performed by our group. 34 Briefly, each part was parametrized under CHARMM General force field philosophy, 35 by using PARAMCHEM platform and the Force Field Toolkit plugin (ffTK) 36 belonging to VMD software. 37 G2-S16 Dendrimer−Protein Docking Simulations.…”

Section: ■ Experimental Proceduresmentioning

confidence: 99%

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Anionic Carbosilane Dendrimers Destabilize the GP120-CD4 Complex Blocking HIV-1 Entry and Cell to Cell Fusion

et al. 2018

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Cell-to-cell transmission is the most effective pathway for the spread of human immunodeficiency virus (HIV-1). Infected cells expose virus-encoded fusion proteins on their surface as a consequence of HIV-1 replicative cycle that interacts with noninfected cells through CD4 receptor and CXCR4 coreceptor leading to the formation of giant multinucleated cells known as syncytia. Our group previously described the potent activity of dendrimers against CCR5-tropic viruses. Nevertheless, the study of G1-S4, G2-S16, and G3-S16 dendrimers in the context of X4-HIV-1 tropic cell-cell fusion referred to syncytium formation remains still unknown. These dendrimers showed a suitable biocompatibility in all cell lines studied and our results demonstrated that anionic carbosilane dendrimers G1-S4, G2-S16, and G3-S16 significantly inhibit the X4-HIV-1 infection, as well as syncytia formation, in a dose dependent manner. We also demonstrated that G2-S16 and G1-S4 significantly reduced syncytia formation in HIV-1 Env-mediated cell-to-cell fusion model. Molecular modeling and in silico models showed that G2-S16 dendrimer interfered with gp120-CD4 complex and demonstrated its potential use for a treatment.

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Section: Methodsmentioning

confidence: 99%

Section: ■ Experimental Proceduresmentioning

confidence: 99%

Anionic Carbosilane Dendrimers Destabilize the GP120-CD4 Complex Blocking HIV-1 Entry and Cell to Cell Fusion

et al. 2018

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“…All the studied drugs showed to effectively interact with the dendrimer in an exothermic fashion, with bleomycin, orlistat and porfimer being the ones that most strongly interact with the PAMAM dendrimer (Radhika et al, 2010). Recently, classic full-atom MD simulations were also used to study interaction of peptide-like drugs and dendrimers, which provide an atomic view of experimental observations in terms of increase of drug half-life and importance of the amino acid composition of the peptide in the interaction with the carrier (Figure 5; Marquez-Miranda et al, 2017;Sepulveda-Crespo et al, 2016).…”

Section: Evaluating Np-drug Interaction and Releasementioning

confidence: 99%

“…(l) Binding energy of each dendrimer/peptide complex obtained from MM‐GBSA method. Obtained with permission from Vacas‐Córdoba et al ()…”

Section: Drug Deliverymentioning

confidence: 99%

Integration of target discovery, drug discovery and drug delivery: A review on computational strategies

Duarte

Márquez-Miranda

Miossec

et al. 2019

WIREs Nanomed Nanobiotechnol

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Most of the computational tools involved in drug discovery developed during the 1980s were largely based on computational chemistry, quantitative structureactivity relationship (QSAR) and cheminformatics. Subsequently, the advent of genomics in the 2000s gave rise to a huge number of databases and computational tools developed to analyze large quantities of data, through bioinformatics, to obtain valuable information about the genomic regulation of different organisms. Target identification and validation is a long process during which evidence for and against a target is accumulated in the pursuit of developing new drugs. Finally, the drug delivery system appears as a novel approach to improve drug targeting and releasing into the cells, leading to new opportunities to improve drug efficiency and avoid potential secondary effects. In each area: target discovery, drug discovery and drug delivery, different computational strategies are being developed to accelerate the process of selection and discovery of new tools to be applied to different scientific fields. Research on these three topics is growing rapidly, but still requires a global view of this landscape to detect the most challenging bottleneck and how computational tools could be integrated in each topic. This review describes the current state of the art in computational strategies for target discovery, drug discovery and drug delivery and how these fields could be integrated. Finally, we will discuss about the current needs in these fields and how the continuous development of databases and computational tools will impact on the improvement of those areas. This article is categorized under:Therapeutic Approaches and Drug Discovery > Emerging Technologies Therapeutic drug delivery, drug discovery, target discoveryThe emergence of new computational technologies has had a significant impact on modern science, serving as a substantial contribution to scientific research. The primary goal of these new tools is to accelerate the process of research, using available computational resources, in different areas such as chemistry and biological biotechnology, among others, on such magnitude that they surpass human discernment. In this context, beginning in 1960, several scientists began to develop theories relating to molecular evolution, laying the basis for bioinformatics by publishing the first Atlas of Protein Sequences; this work is the

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“…Next, we should mention modeling of the cationic or anionic dendrimers, which are extensively studied as multi-functional drug carriers [ 56 , 57 ] in complexes with different proteins: immunoglobulins [ 58 ], amyloidogenic prion protein [ 59 ], actin [ 60 ], human serum albumin [ 61 ], HIV-derived peptides [ 62 , 63 ], ferritin [ 64 ], and other proteins [ 65 ]. Interestingly, control of protonation state (and therefore the net charge) of polyamidoamine (PAMAM) dendrimers allowed control of their interaction with cytolysin A, a protein toxin forming pores in cell membrane and thus causing membrane permeabilization [ 66 ].…”

Section: Protein Interaction With Model Polymers and Nucleic Acidsmentioning

confidence: 99%

Protein Interaction with Charged Macromolecules: From Model Polymers to Unfolded Proteins and Post-Translational Modifications

Semenyuk

Muronetz

2019

IJMS

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Interaction of proteins with charged macromolecules is involved in many processes in cells. Firstly, there are many naturally occurred charged polymers such as DNA and RNA, polyphosphates, sulfated glycosaminoglycans, etc., as well as pronouncedly charged proteins such as histones or actin. Electrostatic interactions are also important for “generic” proteins, which are not generally considered as polyanions or polycations. Finally, protein behavior can be altered due to post-translational modifications such as phosphorylation, sulfation, and glycation, which change a local charge of the protein region. Herein we review molecular modeling for the investigation of such interactions, from model polyanions and polycations to unfolded proteins. We will show that electrostatic interactions are ubiquitous, and molecular dynamics simulations provide an outstanding opportunity to look inside binding and reveal the contribution of electrostatic interactions. Since a molecular dynamics simulation is only a model, we will comprehensively consider its relationship with the experimental data.

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Effect of Several HIV Antigens Simultaneously Loaded with G2-NN16 Carbosilane Dendrimer in the Cell Uptake and Functionality of Human Dendritic Cells

Cited by 8 publications

References 26 publications

Anionic Carbosilane Dendrimers Destabilize the GP120-CD4 Complex Blocking HIV-1 Entry and Cell to Cell Fusion

Anionic Carbosilane Dendrimers Destabilize the GP120-CD4 Complex Blocking HIV-1 Entry and Cell to Cell Fusion

Integration of target discovery, drug discovery and drug delivery: A review on computational strategies

Protein Interaction with Charged Macromolecules: From Model Polymers to Unfolded Proteins and Post-Translational Modifications

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