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Lipid-enveloped viruses, including HIV-1 and SARS-CoV-2, infect their host cells by fusion either directly with the plasma membrane or with the endosome membrane following endocytosis. Biophysical insights into the conformational changes of viral fusion proteins have led to the development of peptide inhibitors of these changes, and hence of membrane fusion. The peptide T-20 (Enfuvirtide) inhibits HIV-1-cell fusion and is being used clinically. The cholesterol-conjugated C34 peptide has an IC₅₀ of 4 pM for inhibiting HIV-1 infectivity, much lower than that of plain C34 and T-20. A peptide (P155-185-chol) corresponding to a segment of the post-fusion structure of influenza virus hemagglutinin, also coupled to cholesterol, inhibits infection by the A/H3N2 subtype with an IC₅₀ of 0.4 μM. Myrcludex B, a myristoylated lipopeptide, inhibits the entry of hepatitis B virus and hepatitis D virus into hepatocytes with an IC₅₀ of 80 pM. Dimer peptides (HRC2 and HRX4) derived from the measles virus F-protein and coupled to cholesterol inhibit measles virus infection at IC₅₀ values of less than 1 nM to 2 nM. Peptides derived from the E protein of Japanese encephalitis virus inhibit infection at nanomolar IC₅₀ values.

 The COVID-19 pandemic has prompted numerous studies to design peptide inhibitors of the SARS-CoV-2 spike protein-mediated membrane fusion. The coupling of a lipidic anchor like cholesterol to some of these peptides enhances the antiviral effect of the peptides, lowering the IC₅₀ to low nanomolar concentrations. It is highly likely that peptides against SARS-CoV-2 will soon be evaluated in clinical trials.