Virion model

Many of the picornavirus structures have been shown to have electron density in their VP1 pockets even in the absence of any added drug. These densities have been modeled as fatty acids or similar compounds [12,15,56,70-72]. The occurrence of these pocket factors have led some to hypothesize that these factors perform a similar function as do capsid-binding inhibitors, that is, to stabilize the virions [15,24,41,73,74]. 

The idea that an inhibitor that binds to a nonenzymatic, nonreceptor site of a virion could inhibit viral replication in vivo would a priori be considered to be an unlikely scenario by most in the field of stmcture-based design. If this idea were proposed knowing only the structure of the native vims (especially HRV14, which has a closed-pocket conformation) skepticism would abound. This type of project arose not from a stmcture-based approach, but from the tried-and-tme screening approach. The compounds were first shown to be effective in inhibiting viral replication in vitro [52]. This was followed by an experiment showing that these compounds could inhibit at least one enterovims in a mouse model [94]. 

Three nearest neighbors, indexed as 0, 6, and 11, are indicated. The axial slab shown represents 1% of the total length of the virion. From Marvin.31a (B) A 2.0 nm section through the virus coat with the helices shown as curved cylinders. The view is down the axis from the N-terminal ends of the rods. The rods extend upward and outward. The rods with indices 0 to -4 start at the same level, forming a five-start helical array. The rods with more negative indices start at lower levels and are therefore further out when they are cut in this section. (C) The same view but with "wire models" of the atomic structure of the rods. From Marvin et al 2... 

A certain class of virus capsides (protein shells of virions) have a spherical structure, that is modeled on dual GCk,i(Dodecahedron) (see [CaK162, Cox71, DDG98]). 

Prasad and Prevelige, Fig. 3. Summary of the architectural features of rotavirus, a prototypical member of the Reoviridae family, (a) Cutaway of the mature virion structure, showing the locations of the various structural proteins, (b) Cutaway of the transcriptionally competent double-layered particle, showing the RNA core. (c). Structure of actively transcribing rotavirus double-layered particles, (d) Close-up of the exit pathway of the mRNA during transcription (Lawton et at, 1997). (e) Model for the organization of the RNA segments (Pesavento et at, 2001). 

While our studies of NC protein alone demonstrated little if any crosslinking, the results with HIV-1 virus showed extensive oligomerization. The mature virion contains a compact ribonucleoprotein complex formed by the genomic RNA and ca. 2,500 copies of the NC protein. Therefor the high concentration of NC in the viral particle the formation of intermolecular disulfide bonds over intramolecular ones is expected to be favored following virus treatment with thiuram disulfides. In agreement with this model, the reaction of tetraethylthiuram disulfide with concentrated samples of HIV-1 NC protein in vitro lead to extensive p7 oligomerization. Such crosslinked macromolecular structures appear likely... 

Figure 3-16 Model of bacteriophage fd engineered to display peptides as inserts in the coat proteins of the virus. The native virus structure is shown in gray proteins not present in the native virus are shown black or green, inserted near the N-termini of some major coat proteins is a 6-residue peptide. To one of these peptides a specific Fab antibody fragment (green) has bound from solution, and a second Fab is shown nearby. The N-terminal region of a minor coat protein at the end of the virion has been engineered to display a (different) Fab fragment. Steric constraints are less stringent for inserts in the minor proteins, but fewer copies per virion are possible. Reprinted with permission from Barbas, et...

In Figure 2, kinetics of T2 removal using QAC treated beads is presented. It is obvious that the competitive adsorption between viruses and BSA molecules also reduced the adsorption rate. In both cases, viruses were inactivated rapidly at the initial 2 hour mark and titer reduction slowed down after that. This inconsistency with the first-order inactivation model may be due to various interfering mechanisms such as displacement, molecular orientation, multilayer effects, surface heterogeneity, and virion clumping. 

The number of virions (viral load) in the blood is currently the major endpoint that is used to evaluate the efficacy of antiviral drugs. Therefore, mathematical modeling of the viral dynamics early in the treatment can provide a good indication of the effectiveness of the drug and, in some cases (e.g., in the treatment of hepatitis C), the duration of treatment required. In the future, we may see the use of viral dynamic models in optimizing drug combinations. 

Viral dynamic modeling has been described for the effects of two classes of anti-HIV drugs, namely, reverse-transcriptase inhibitors (RTIs) that prevent infection of new cells and protease inhibitors (Pis) that decrease production of infectious virions by blocking the release of virions from infected cells, leading to the production of... 

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