Bruce Merrifield's contribution to antimicrobial peptide research

Abstract

Although within the scientific community at large Bruce Merrifield is and will remain celebrated for the pivotal discovery and dedicated crafting of solid phase peptide synthesis methodology, there are also other areas where his unique scientific acumen was applied to with distinctive success. Among them, those of glucagon antagonists and antimicrobial peptides are arguably the better known. Over my 25 year-long relationship with Bruce, I had occasion to work with him in both areas, but it is to the latter I will devote these brief reminiscences, as our collaboration in this fast expanding research field reached from its very dawn till relatively recently. 2006, the year of Bruce’s passing, marked the silver jubilee of antimicrobial peptide research, officially initiated with the publication of the seminal paper on the cecropins by Boman (see Figure 1) and coworkers. 1 Hans had befriended Bruce during his postdoc (1958–60) in Fritz Lipmann’s group at Rockefeller, and his logical enthusiasm over the finding of a family of eukaryotic, geneencoded peptides with remarkably potent antimicrobial activities must have been contagious for Bruce, who started to collaborate with Hans on the cecropins in late 1981. On joining Bruce’s lab in January 1982, the very first project given to me was to synthesize the putative 37-residue sequence of cecropin A, to confirm some structural assignations tentatively proposed for the C-terminal region. A previous synthetic attempt 2 had turned out an active compound, albeit nonidentical with the natural peptide. Building on that result and benefiting from several improvements emanating at the time from Bruce and Jimmy Tam’s joint research—not least the very useful high-low HF cleavage method 3 —I completed my assignment in two-and-a-half months, which at the time was regarded a reasonable time for a relative novice charged with the fully manual synthesis of a 37-residue, tritiumlabeled peptide. Our synthetic product was completely identical with the native peptide by microbiological as well as biochemical (enzyme digest + HPLC) criteria, and we were able to confirm the hitherto uncertain structure of the C-terminal end by means of plasma desorption MS, a forerunner of modern MALDI-TOF MS. In addition, our report 4 discussed the relevance of the Trp-2 residue for antimicrobial activity and thus set the basis for further analogue work. 5 In retrospect, that initial 2-year stint in the cecropin project appears as a decisive period, where Bruce’s gracious support and encouragement became the beacon blazing away the often usual angst of a nascent scientific career. A thorough and constructive draft reviewer if ever I saw one, Bruce returned each one of my versions generously endowed with pencil scribbles which, readily deciphered, brought gradual improvement to my struggling manuscripts. To Bruce I owe a great deal of any abilities I may have achieved as a (non-native) writer of English scientific texts. Those early 1980s cecropin manuscripts, first examples of the substantial contri