1.G.8 The Arenavirus Fusion Protein (AV-FP) Family

Arenaviruses are important agents of zoonotic disease worldwide. The virions expose a tripartite envelope glycoprotein complex at their surface, formed by the glycoprotein subunits GP1, GP2 and the stable signal peptide. This complex is responsible for binding to target cells and for the subsequent fusion of viral and host-cell membranes for entry. During this process, the acidic environment of the endosome triggers a fusogenic conformational change in the transmembrane GP2 subunit of the complex. Igonet et. al (2011) reported the crystal structure of the recombinant GP2 ectodomain of the lymphocytic choriomeningitis virus, the arenavirus type species, at 1.8-Å resolution. The structure shows the characteristic trimeric coiled coil present in class I viral fusion proteins, with a central stutter that allows a close structural alignment with most of the available structures of class I and III viral fusion proteins. The structure further shows a number of intrachain salt bridges stabilizing the postfusion hairpin conformation, one of which involves an aspartic acid that appears released from a critical interaction with the stable signal peptide upon low pH activation.

The mature arenavirus envelope glycoprotein complex (GPC) is a tripartite complex comprising a stable signal peptide (SSP) in addition to the receptor-binding (G1) and transmembrane fusion (G2) subunits. SSP is a key element in GPC-mediated membrane fusion, and GPC sensitivity to acidic pH is modulated in part through the lysine residue at position 33 in the ectodomain loop of SSP (York and Nunberg, 2009). A glutamine substitution at this position stabilizes the native GPC complex and thereby prevents the induction of pH-dependent membrane fusion. The pH-dependent interaction is vulnerable to small compounds that stabilize the native complex and prevent the activation of membrane fusion.



Cao, J., S. Dong, Y. Liu, M. Zhou, J. Guo, X. Jia, Y. Zhang, Y. Hou, M. Tian, G. Xiao, and W. Wang. (2021). Screening and Identification of Lujo Virus Entry Inhibitors From an Food and Drug Administration-Approved Drugs Library. Front Microbiol 12: 793519.

Igonet, S., M.C. Vaney, C. Vonhrein, G. Bricogne, E.A. Stura, H. Hengartner, B. Eschli, and F.A. Rey. (2011). X-ray structure of the arenavirus glycoprotein GP2 in its postfusion hairpin conformation. Proc. Natl. Acad. Sci. USA 108: 19967-19972.

York, J. and J.H. Nunberg. (2009). Intersubunit interactions modulate pH-induced activation of membrane fusion by the Junin virus envelope glycoprotein GPC. J. Virol. 83: 4121-4126.


TC#NameOrganismal TypeExample

Preglycoprotein polyprotein (GP) complex. Contains (1) regional peptide, (2) GPI, and (3) GP2. (2 N-terminal TMSs) (Igonet et al., 2011).


GP2 of Lymphocytic choriomeningitis virus (P09991)


Pre-glycoprotein polyprotein (precursor), GPC (York and Nunberg, 2009).


Pre-GPC of Junin virus (P26313)


Glycoprotein precursor, partial, of 225 aas.

GP precursor of Middle Pease River virus


Glycoprotein precursor, partial of 235 aas.

Gp precursor of Gairo mammarenavirus


Glycoprotein precursor, GPC, of Lujo mammarenavirus of 454 aas and 2 - 5 TMSs with 1 - 3 TMSs N-terminal and 1 TMS C-terminal. Lujo virus (LUJV) belongs to the Old World (OW) genus Mammarenavirus (family Arenaviridae), a biosafety level (BSL) 4 agent (Cao et al. 2021). A high-throughput screening of an FDA-approved drug library was conducted using pseudotype viruses bearing LUJV envelope glycoprotein (GPC) to identify inhibitors of LUJV entry. Three hit compounds, trametinib, manidipine, and lercanidipine, were identified as LUJV entry inhibitors in the micromolar range. Mechanistic studies revealed that trametinib inhibited LUJV GPC-mediated membrane fusion by targeting C410 [located in the transmembrane domain], while manidipine and lercanidipine inhibited LUJV entry by acting as calcium channel blockers. All three hits extended their antiviral spectra to the entry of other pathogenic mammarenaviruses, and all three could inhibit the authentic prototype mammarenavirus, lymphocytic choriomeningitis virus (LCMV), and could prevent infection at the micromolar level (Cao et al. 2021).

GPC of Lujo mammarenavirus