Background The C-terminal domain (CTD) of HIV-1 capsid (CA), like full-length
Background The C-terminal domain (CTD) of HIV-1 capsid (CA), like full-length CA, forms dimers in solution and CTD dimerization is a major driving force in Gag assembly and maturation. formation. In in vitro assembly assays, the peptides inhibited mature-like virus particle formation and specifically inhibited HIV-1 production in cell-based assays. These peptides also showed potent antiviral activity against a large panel of laboratory-adapted and primary isolates, including viral strains resistant to inhibitors of reverse transcriptase and protease. Conclusions These preliminary data buy Ro 90-7501 serve as the foundation for buy Ro 90-7501 designing small, stable, -helical peptides and small-molecule inhibitors targeted against the CTD dimer interface. The observation that relatively weak CA binders, such as NYAD-201 and NYAD-202, showed specificity and are able to disrupt the CTD dimer is encouraging for further exploration of a much broader class of antiviral compounds targeting CA. We cannot exclude the possibility that the CA-based peptides described here could elicit additional effects on virus replication not directly linked to their ability to bind CA-CTD. Background During HIV-1 assembly and morphogenesis, the structural protein, Gag, organizes into two completely different arrangements, immature and mature forms. In the immature form, Gag remains intact, whereas in the Rabbit polyclonal to GAD65 mature form, Gag is cleaved by the viral protease (PR). The formation of this mature particle is essential for HIV-1 infectivity and the capsid protein (CA) obtained from the Gag cleavage product plays a central role in forming the conical virion core that surrounds the viral genome. The CA protein consists of two domains, the N-terminal domain (NTD, aa 1-145) and the C-terminal domain (CTD, aa 151-231). These two domains are connected by a 5-amino-acid buy Ro 90-7501 linker. The CA-CA contacts in buy Ro 90-7501 both immature and mature particles have been modeled based on X-ray structures of isolated domains and image reconstructions by cryo-electron microscopy of mature virions and assembled virus-like particles (VLPs) [1-8]. Recently, a pseudo-atomic model of the full-length HIV-1 CA hexameric structure was reported, which provided structural insights on the mechanism of action of some known assembly inhibitors [5,7,9]. HIV-1 CA plays a crucial role in viral assembly, maturation and also early post-entry steps [1-4,6,8]. Mutations in buy Ro 90-7501 both the NTD and CTD lead to defects in viral assembly and release [10-21]. Taken together, it is evident that CA plays an important role in HIV-1 assembly and maturation, and has been recognized as a potential target for developing a new generation of drugs for AIDS therapy [22-27]. The NTD of CA binds to cyclophilin A [28,29] and is important for viral core formation. However, critical determinants of Gag oligomerization, essential for viral assembly, are located in the CTD . In addition, the CTD encompasses the most conserved segment of Gag known as the major homology region (MHR). Mutation of retroviral CA MHRs leads to severe defects in viral assembly, maturation and infectivity [19,31-37]. The isolated CTD of HIV-1 CA, like full-length CA, forms a dimer in solution. It has been shown that CTD dimerization is a major driving force in Gag assembly and maturation [10,15]. Several structures of the CTD dimer have been reported, providing critical information on the dimer interface [38-41]. Mutation of the interface residues in the CTD monomer disrupts dimer formation , impairs CA assembly and abolishes virus infectivity [10,15]. The CTD therefore plays an important role in viral assembly and maturation and is a potential target for developing a new class of anti-HIV-1 drugs [6,43]. Protein-protein interactions play a key role in a range of biological processes such as antigen-antibody interaction [44-46], viral assembly, programmed cell death, cell differentiation and signal transduction. Therefore, controlling these vast arrays of interactions offers opportunities for developing novel therapeutic agents. However, inhibiting these processes by traditional drug discovery techniques may be complicated and challenging due to the shallow binding interfaces and relatively large interfacial areas involved in most.