However, the domains encompassing these peptides, IIb and the pre-anchor stem, are likely involved in structural rearrangements within the fusion protein during the fusion process, rather than in direct interactions with cellular receptors. prove efficient in multidrug combinations, in order to inhibit several steps of virus life cycle and prevent disease progression. their envelope proteins. In the case of a pH-independent entry, this initial binding leads to conformational changes of the envelope fusion protein, eventually exposing the fusion peptide. Insertion of this peptide into the plasma membrane allows fusion between viral and plasma membranes, and release of the virus genome into the cytoplasm. Membrane fusion of viruses displaying pH-dependent entry occurs within the SR 59230A HCl acidic environment of endosomal compartments, where the pH induces the conformational changes of the fusion protein leading to the exposure of the fusion peptide. All these stages are potentially amenable to therapeutic intervention. In this review, we will therefore discuss the various possible targets in the context of recently developed antiviral molecules. The knowledge and understanding of antiviral strategies studied or applied for enveloped viruses could lead to the development of new inhibitors. Three Classes of Viral Fusion Proteins Viral envelope proteins have two functions: the specific attachment to the SR 59230A HCl cell and membrane fusion. These two functions could involve one or more proteins. Viral fusion proteins are defined as three classes, mainly depending on structural features [2,3,4,5]. Fusion proteins of these three classes display different architectures but they adopt during fusion a similar overall hairpin conformation [5] (Figure 2 and Figure 3). However, for many virus families, structural information is still missing to identify and classify their membrane fusion proteins. Open in a separate window Open in a separate window Figure 2 Conformation of enveloped virus proteins of classes I and II. Open in a separate window Figure 3 Schematic structure of HIV gp41 in pre- and post-fusion conformations. Class I proteins mostly contain alpha-helical structures and the hydrophobic fusion peptide is located at the N-terminus, buried within the protein core. These proteins associate as homotrimers that project vertically from the viral membrane. This group includes proteins of several viral families as (Human Immunodeficiency Virus HIV, gp41), (Influenza virus, HA protein(Respiratory Syncytial Virus RSV, F protein), (Ebola, GP2 protein) and (Coronavirus, S protein) [5]. Viruses with class I fusion proteins share a common mechanism of fusion, mediated by a glycoprotein that contains two hydrophobic heptad repeats SR 59230A HCl in its extracellular domain, which are central to the complex conformational changes leading to fusion. The first heptad repeat (HR1 or HRN) is adjacent to the fusion peptide, while the second (HR2 or HRC) immediately precedes NR2B3 the transmembrane domain (Figure 2). Once fusion is triggered, these domains drastically rearrange to form highly structured and thermodynamically stable coiled-coils of three HR1 heptad repeats in a prefusion stalk conformation. This intermediate allows the fusion peptide to be exposed and eventually inserted into the membrane of the target cell. In the final stage of membrane fusion, the pre-hairpin spontaneously collapses into the post-fusion structure – a six-helical bundle (6HB), with the inner trimeric coiled coil formed by the HR1 onto which the SR 59230A HCl HR2 folds (Figure 2). This results in membrane merging and formation of a stable fusion pore [7,8,9]. Concerning HIV, envelope proteins are arranged as two non covalently-linked glycoproteins, gp120 (function of attachment) and gp41 (function of fusion), forming trimeric spikes projecting SR 59230A HCl from the lipid viral envelope [10] (Figure 3). To enter the cell, HIV specifically binds to the host protein receptor CD4 its gp120 subunit [11,12]. CD4 binding induces a conformational change exposing an otherwise cryptic binding site on the gp120 molecule for one of the two major HIV coreceptors, CCR5 or CXCR4. Coreceptor binding triggers conformational changes in gp120 and gp41, resulting in the exposure of the fusion peptide, its insertion into the plasma membrane and the association of HR2 domains with the HR1 trimer, to form a hairpin structure forming the thermodynamically stable 6HB (Figure 3). This allows membrane fusion and the release of the genome of HIV directly in the cell cytoplasm. Interestingly, cholesterol-enriched lipid microdomains of the plasma membrane seem required for HIV cell entry [13]. Two viral glycoproteins are involved in cell infection by the respiratory syncytial virus (RSV): an attachment protein (G) and the fusion protein (F) [14,15]. These proteins bind to heparin.