Of minibody, camel and bacteriophage.
This review describes the design process from conception through realisation and optimisation of a minibody'--a minimised antibody. The result was a proteinaceous molecule of novel fold and metal binding activity. We explain how combinatorial approaches, using phage display libraries, were used to randomise loop regions of the minibody. Variants were then selected for desired activities including in vitro inhibition of human interleukin-6 and the protease of the non-structural protein, NS3, of the hepatitis C virus. One such variant was successfully minimised further to produce a cyclic peptide with similar inhibition properties. Thus the work reviewed provides examples of two important processes in protein design and protein minimisation. We conclude by discussing the role of such studies in medical applications and small molecule drug discovery. We also highlight the potential of our work and similar techniques in the post-genomic era.
Vaughan
C K
CK
I.R.B.M. P. Angeletti, Via Pontina km 30.600, Roma, 00040, Italy.
Sollazzo
M
M
D000595:Amino Acid Sequence; D000818:Animals; D000906:Antibodies / Q000737:chemistry* / Q000235:genetics; D001435:Bacteriophages / Q000235:genetics*; D020650:Combinatorial Chemistry Techniques; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D006868:Hydrolysis; D015850:Interleukin-6 / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D051379:Mice; D008969:Molecular Sequence Data; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid; D012995:Solubility; D021241:Spectrometry, Mass, Electrospray Ionization; D017361:Viral Nonstructural Proteins / Q000737:chemistry / Q000187:drug effects / Q000235:genetics; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D000906:Antibodies; D004791:Enzyme Inhibitors; D015850:Interleukin-6; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases