A chemical approach to the pharmaceutical optimization of an anti-HIV protein.
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.
Miranda
Les P
LP
Gryphon Therapeutics, 600 Gateway Boulevard, South San Francisco, California 94080, USA. lesm@amgen.com
Shao
Haiyan
H
Williams
Jason
J
Chen
Shiah-Yun
SY
Kong
Ting
T
Garcia
Rod
R
Chinn
Yvonne
Y
Fraud
Nathalie
N
O'Dwyer
Bill
B
Ye
Jay
J
Wilken
Jill
J
Low
Donald E
DE
Cagle
E Neil
EN
Carnevali
Maia
M
Lee
Alexander
A
Song
Di
D
Kung
Ada
A
Bradburne
James A
JA
Paliard
Xavier
X
Kochendoerfer
Gerd G
GG
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
D000596:Amino Acids; D019380:Anti-HIV Agents; D015483:HIV Antibodies; D054298:Human Immunodeficiency Virus Proteins; D011108:Polymers; D043562:Receptors, G-Protein-Coupled