Tag Archives: unnatural amino acids

Antibodies without antibodies

If you knew exactly how an important class of antibodies interacted with its target, could you design a (relatively) small molecule to act the same way.  These people did, and the work has very exciting implications for infectious disease [ Science vol. 358 pp. 450 – 451, 496 – 502 ’17 ].

The influenza virus is a very slippery target.  Its genome is made of RNA, and copying it is quite error prone, so that mutants are formed all the time.  That’s why the vaccines of yesteryear are useless today.   However there are things called broadly neutralizing antibodies which work against many strains of the virus.  It attacks a vulnerable site on the hemagglutinin protein (HA) of the virus.  It is in the stem of the virus, and binding of the antibody here prevents the conformational change required for the virus to escape the endosome, a fact interesting in itself in that it implies that it only works after the virus enters the cell, although the authors do not explicitly state this.

Study of one broadly neutralizing antibody showed that binding to the site was mediated by a single hypervariable loop.  So the authors worked with a cyclic peptide mimicking the loop.  This has several advantages, in particular the fact that the entropic work of forcing a floppy protein chain into the binding conformation is already done before the peptide meets its target.

The final cyclic peptide contained 11 amino acids, of which 5 weren’t natural. It neutralized pandemic H1 and avaian H5 influenza A strains at nanoMolar concentration.

It’s important that crystal structures of the broadly neutralizing antibody binding to HA were available — this requires atomic level resolution.  I’m not sure cryoEM is there yet.