Fig 1.
LHF-535 is a small-molecule compound of the bis-substituted benzimidazole class.
Table 1.
Sensitivity of envelope glycoproteins to viral entry inhibitors.
Fig 2.
The Lassa virus LP strain contains two unique amino acid substitutions in the transmembrane domain of the GP2 subunit.
The amino acid sequence shown is GP 417–448 of lineage IV and 416–447 for all others; previously identified sensitivity determinants are bulleted [12], the predicted transmembrane domain (TMD) is underlined, and the two distinguishing residues of the LP strain (I432 and I434) are in bold.
Table 2.
LHF-535 sensitivity of engineered Lassa and Junín virus GPs.
Table 3.
LHF-535 exhibits differential potency in virus yield reduction assay.
Fig 3.
LHF-535 protects AG129 mice against lethal Tacaribe virus challenge.
Mice were challenged with 200 plaque-forming units (PFU) of Tacaribe virus by intraperitoneal injection. Mice received daily oral doses of LHF-535 (3, 10, or 30 mg/kg) or vehicle alone beginning 0.5 h prior to challenge until 13 days post-challenge. One cohort (n = 8 animals per group) was monitored for survival (A), while another cohort (n = 4 animals per group) was sacrificed at 7 days post-challenge to measure viral titers in plasma (B), spleen (C), and liver (D). The virus detection limit is indicated by a dashed line.
Fig 4.
LHF-535 is effective as a post-exposure therapeutic in mice.
AG129 mice (n = 10 per group) were challenged with Tacaribe virus as in Fig 3 and received daily oral doses of LHF-535 (10 mg/kg) beginning 0.5 h before, or 24, 48, or 72 h after viral challenge. All groups received their last dose at 13 days post-challenge. The control group was treated with vehicle alone using the same dosing regimen as the group receiving LHF-535 0.5 h prior to viral challenge.
Fig 5.
The LHF-535-resistant Tacaribe virus variant F425L is attenuated in AG129 mice and protects against subsequent challenge with the virulent wild-type virus.
(A) LD50 study with F425L (n = 6 per group). (B) LD50 study with Tacaribe virus (n = 6 per group). (C) Mice (n = 5) infected with F425L (2,000 PFU) were challenged 31 days later with wild-type Tacaribe virus (200 PFU). Age-matched naïve mice (n = 6) were infected with wild-type Tacaribe virus (200 PFU) as a control.
Table 4.
LHF-535 sensitivity and pathogenicity of variants.