Synthetic bivalent CD4-mimetic miniproteins show enhanced anti-HIV activity over the monovalent miniprotein.
HIV-1 envelope glycoprotein gp120 is displayed as a trimeric complex on the surface of virion and infected T-cells, making it a typical multivalent target. This paper describes the design and synthesis of bivalent CD4-mimetic miniproteins to target the conserved CD4-binding pockets in the trimeric gp120. Using miniprotein CD4M9 as the model inhibitor, we created bivalent inhibitors in which two CD4M9 moieties were tethered by a spacer of varied length and evaluated their anti-HIV activity using a cell culture assay. The synthetic bivalent miniproteins showed 5-21-fold enhancement in anti-HIV activity over the monovalent miniprotein. The activity enhancement is dependent on the length of the spacer. The study suggests that targeting the oligomeric gp120 complex by novel multivalent ligands offers a valuable strategy for developing highly specific and effective HIV entry inhibitors.
Li
Hengguang
H
Institute of Human Virology, University of Maryland Biotechnology Institute, University of Maryland, Baltimore 21201, USA.
Song
Haijing
H
Heredia
Alonso
A
Le
Nhut
N
Redfield
Robert
R
Lewis
George K
GK
Wang
Lai-Xi
LX
D000163:Acquired Immunodeficiency Syndrome / Q000821:virology; D000595:Amino Acid Sequence; D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D015704:CD4 Antigens / Q000737:chemistry*; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D003545:Cysteine / Q000737:chemistry; D015195:Drug Design; D015699:HIV Envelope Protein gp120 / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology; D006801:Humans; D020128:Inhibitory Concentration 50; D008214:Lymphocytes / Q000187:drug effects / Q000821:virology; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D015394:Molecular Structure; D017510:Protein Folding; D011506:Proteins / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D021241:Spectrometry, Mass, Electrospray Ionization
D019380:Anti-HIV Agents; D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120; D011506:Proteins; D003545:Cysteine