Supercoiling Structure-Based Design of a Trimeric Coiled-Coil Peptide with High Potency against HIV‑1 and Human β‑Coronavirus Infection

Hexameric structure formation through
packing of three C-terminal
helices and an N-terminal trimeric coiled-coil core has been proposed
as a general mechanism of class I enveloped virus entry. In this process,
the C-terminal helical repeat (HR2) region of viral membrane fusion
proteins becomes transiently exposed and accessible to N-terminal
helical repeat (HR1) trimer-based fusion inhibitors. Herein, we describe
a mimetic of the HIV-1 gp41 HR1 trimer, N3G, as a promising therapeutic
against HIV-1 infection. Surprisingly, we found that in addition to
protection against HIV-1 infection, N3G was also highly effective
in inhibiting infection of human β-coronaviruses, including
MERS-CoV, HCoV-OC43, and SARS-CoV-2, possibly by binding the HR2 region
in the spike protein of β-coronaviruses to block their hexameric
structure formation. These studies demonstrate the potential utility
of anti-HIV-1 HR1 peptides in inhibiting human β-coronavirus
infection. Moreover, this strategy could be extended to the design
of broad-spectrum antivirals based on the supercoiling structure of
peptides.