Poxvirus targeted by RFdiffusion peptide-binders

Abstract

Peptide-binders were generated by computational RFdiffusion to the F13L-homodimer interface sequences of poxviruses such as vaccinia and monkeypox. Compared to small-drug screenings and/or co-evolutions, peptide-binders have the advantages of higher affinities and easier chemical / recombinant synthesis. Among the hundreds of 20-30-mer peptide-binders randomly generated by RFdiffusion, some targeted vaccinia (VACV) F13L homodimer interface predicting low nanoMolar affinities. To improve its physiological stability, additional peptide sequences were computationally generated by cyclization/ hallucination. The resulting de novo cyclic peptide sequences predicted picoMolar affinities not only targeting the VACV F13L homodimer interfaces but also inner cavities previously identified by small-drug dockings to Tecovirimat-resistant monkeypox (MPXV) mutants. Because their targeting to numerous highly-conserved amino acids among poxviruses, and improved physiological stability against proteases, cyclic peptide-binders may be more adequate against resistant mutants of VACV and MPXV poxviruses. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=174 SRC="FIGDIR/small/654163v1_ufig1.gif" ALT="Figure 1"> View larger version (72K): org.highwire.dtl.DTLVardef@148a2fborg.highwire.dtl.DTLVardef@1c4117forg.highwire.dtl.DTLVardef@158ea61org.highwire.dtl.DTLVardef@839761_HPS_FORMAT_FIGEXP M_FIG C_FIG