Design and characterization of novel SARS-CoV-2 fusion inhibitors with N-terminally extended HR2 peptides

New star-shaped ligands generated by evolutionary fitting the Omicron spike inner-cavity

“…Such inner-cavity has been implicated in the Omicron early prefusion-fusion switch triggered after human ACE receptor recognition 20,21 . This inner-cavity seems to be highly conserved in Omicron variants, since only three Omicron new mutations (Q954H, N969K, L981F) 22 have been described that could directly affect the prefusion-fusion switch 23 . For this, we started from previous computationally-identified star-shaped triazine-core molecules cross docking the inner-cavity of the SARS-COV-2 wild-type all-down prefusion state isolate of 2021 20,21 .…”

“…Most previous experimental and/or computational search for anticoronaviral molecules has been focused on approved drugs (drug repurposing) [29][30][31] to other protein targets rather to the coronavirus inner-cavity. Most of those earlier works included the inhibition of the S2 coiled-coil bundle by complementary peptides 23,[32][33][34][35] , the blocking of the surface interphase of S1 with the ACE2 human receptor 18,19,36 , and/or the active sites of viral proteases 30,37,38 among others. In contrast, our previous efforts to use ligands rather than mutations 20,21 , explored the inner-cavity.…”

Helix-based screening with structure prediction using artificial intelligence has potential for the rapid development of peptide inhibitors targeting class I viral fusion

“…36 Previous studies of SARS-CoV-2 have reported the importance of the N-terminal amino acids of HR2. 37,38 The results of SPICA also indicated that, for fusion inhibitors against SARS-CoV-2, a disordered region and the stability of the a-helical structure were important to exhibit an antiviral effect (Tables 1 and 2). The importance of the disordered regions was reinforced by the crystal structure (Fig.…”

Chemically modified antiviral peptides against SARS‐CoV‐2

“…Hu et al compared the activity of the native peptide Spike(1164-1203), entirely included in the HR2 region, with a C-terminal analog modified with a PEG 8 spacer and a cholesterol moiety, termed P40 and P40-LP, respectively (Entry 4, Table 2). 74 The antiviral activity of the cholesteryl-derivative is more than 1000-fold higher than the native sequence shifting from a mean IC 50 = 2. As reported above, the formation of 6-HB involves the three helices of the HR1 and HR2 fragments.…”

“…Hu et al compared the activity of the native peptide Spike(1164–1203), entirely included in the HR2 region, with a C‐terminal analog modified with a PEG 8 spacer and a cholesterol moiety, termed P40 and P40‐LP, respectively ( Entry 4, Table 2). 74 The antiviral activity of the cholesteryl‐derivative is more than 1000‐fold higher than the native sequence shifting from a mean IC 50 = 2.32 μM to 1.99 nM, calculated against different SARS‐CoV‐2 variants. In the same direction, Zhu et al designed the cholesteryl‐derivative (without spacer) of the shorter fragment Spike(1169–1203), called IPB02 ( Entry 5, Table 2).…”