title: A chemical approach to the pharmaceutical optimization of an anti-HIV protein.
abstract: Chemical protein synthesis is important for dissecting the molecular basis of protein function. Here we advance its scope by demonstrating the significant improvement of the multifaceted pharmaceutical profile of small proteins exclusively via a chemical-based approach. The focus of this work centered on CCL-5 (RANTES) derivatives with potent anti-HIV activity. The overall chemical strategy involved a combination of coded and noncoded amino acid mutagenesis, peptide backbone engineering, and site-specific polymer attachment. The ability to alter specific protein residues, as well as precise control of the position and type of polymer attachment, allows for the exploration of specific molecular designs and resulted in novel CCL-5 analogues with significant differences in their respective biochemical and pharmaceutical properties. Using this approach, the complex-interplay of variables contributing to the noncovalent self-association (aggregation) state, CCR-5 specificity, in vivo elimination half-life, and anti-HIV activity of CCL-5-based protein analogues could be empirically evaluated via total chemical synthesis. This work has led to the identification of potent (sub-nanomolar) anti-HIV proteins with significantly improved pharmaceutical profiles, and illustrates the increasing value of protein chemical synthesis in contemporary therapeutic discovery. These antiviral molecules provide a novel mechanism of action for the development of a new generation of anti-HIV therapeutics which are still desperately needed.
authors.affiliation: Gryphon Therapeutics, 600 Gateway Boulevard, South San Francisco, California 94080, USA. lesm@amgen.com
authors.forename: Les P
authors.initials: LP
authors.lastname: Miranda
authors.forename: Haiyan
authors.initials: H
authors.lastname: Shao
authors.forename: Jason
authors.initials: J
authors.lastname: Williams
authors.forename: Shiah-Yun
authors.initials: SY
authors.lastname: Chen
authors.forename: Ting
authors.initials: T
authors.lastname: Kong
authors.forename: Rod
authors.initials: R
authors.lastname: Garcia
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Chinn
authors.forename: Nathalie
authors.initials: N
authors.lastname: Fraud
authors.forename: Bill
authors.initials: B
authors.lastname: O'Dwyer
authors.forename: Jay
authors.initials: J
authors.lastname: Ye
authors.forename: Jill
authors.initials: J
authors.lastname: Wilken
authors.forename: Donald E
authors.initials: DE
authors.lastname: Low
authors.forename: E Neil
authors.initials: EN
authors.lastname: Cagle
authors.forename: Maia
authors.initials: M
authors.lastname: Carnevali
authors.forename: Alexander
authors.initials: A
authors.lastname: Lee
authors.forename: Di
authors.initials: D
authors.lastname: Song
authors.forename: Ada
authors.initials: A
authors.lastname: Kung
authors.forename: James A
authors.initials: JA
authors.lastname: Bradburne
authors.forename: Xavier
authors.initials: X
authors.lastname: Paliard
authors.forename: Gerd G
authors.initials: GG
authors.lastname: Kochendoerfer
mesh_terms: D000596:Amino Acids / Q000737:chemistry; D000818:Animals; D019380:Anti-HIV Agents / Q000737:chemistry* / Q000493:pharmacokinetics; D002850:Chromatography, Gel; D015483:HIV Antibodies / Q000276:immunology*; D054298:Human Immunodeficiency Virus Proteins / Q000276:immunology*; D008297:Male; D008958:Models, Molecular; D015394:Molecular Structure; D011108:Polymers / Q000737:chemistry; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism
chemical_list: D000596:Amino Acids; D019380:Anti-HIV Agents; D015483:HIV Antibodies; D054298:Human Immunodeficiency Virus Proteins; D011108:Polymers; D043562:Receptors, G-Protein-Coupled