In vitro and in silico Study of Interferon-Inducing Nucleic Acids Analogs Artifi cially Programmed to Blockage of HIV Entry into Cells
The approaches to the molecular design of antiviral agents based on the principles of adequacy and mimicry to biopolymers has been discussed. The approaches permit to reproduce pharmaceutically valuable properties of the polymeric basis (backbone), and to create novel non-genetic “programs” for bioactivity of macromolecules by means of grafting specific side group combinations to this backbone. In the in vivo experiments, it was shown that the immunostimulating (in particular, interferon-inducing) antiviral potency of nucleic acids (NA) is characteristic of carboxylic-acid analogs having a NA-like order of furan and anionic components alteration in the polymeric chain. A controlled grafting of virus-targeted side groups to the polymeric basis led to the direct blockage of viral infection in vitro as an additional antiviral effect. In this work, the inhibitors of the early stages of the human immunodeficiency virus type 1 (HIV-1) penetration in cells have been studied. A modeling of the macromolecules interaction with the most probable target, the virus—cell fusion mediator (an a-helical complex of N-region of repeated aminoacid heptades of three HIV-1 envelope glycoprotein gp41 trans-membrane molecules) was performed. The computational docking experiment in silico resulted in the clarification of the putative mechanisms and parameters for programming of site-tropic, axial and belting blockage of the target via the alicyclic type side-groups application. The discovered opportunities of multi-point axi-al-co-belting blockage ofthe target opens up new prospects to the prevention/therapy of AIDS, as well as of other viral infections that use similar systems of envelope fusion peptides (of 1 <sup>s+</sup> and 3 <sup>nd</sup> types) for penetration in cells.