Carbonylhydrazide-based molecular tongs inhibit wild-type and mutated HIV-1 protease dimerization.
We have designed and synthesized new molecular tongs based on a rigid naphthalene scaffold and evaluated their antidimer activity on HIV-1 protease (PR). We inserted carbonylhydrazide and oligohydrazide (azatide) fragments into their peptidomimetic arms to reduce hydrophobicity and increase metabolic stability. These fragments are designed to disrupt the protein-protein interactions by reproducing the hydrogen bond pattern found in the antiparallel β-sheet formed between the N- and C-ends of the two monomers in the native PR. Kinetic analyses and fluorescent probe binding studies showed that several molecular tongs can inhibit PR dimerization. The best nonpeptidic molecular tongs to date were obtained with an inhibition constant K(id) of 50 nM for PR and 80 nM for the multimutated protease ANAM-11. The PR inhibition was selective, the aspartic proteases renin and pepsin were not inhibited.
UMR-CNRS 8076, Molécules Fluorées et Chimie Médicinale, LabEx LERMIT, Faculté de Pharmacie, Université Paris-Sud 11, 5 rue J. B. Clément, 92296 Châtenay-Malabry Cedex, France.
Laure
L
Dufau
Ana Sofia
AS
Marques Ressurreição
Roberto
R
Fanelli
Nadjib
N
Kihal
Anamaria
A
Vidu
Thierry
T
Milcent
Jean-Louis
JL
Soulier
Jordi
J
Rodrigo
Audrey
A
Desvergne
Karine
K
Leblanc
Guillaume
G
Bernadat
Benoit
B
Crousse
Michèle
M
Reboud-Ravaux
Sandrine
S
Ongeri
D057075:Enzyme Assays; D005470:Fluorometry; D016333:HIV Protease / Q000737:chemistry* / Q000235:genetics; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D006834:Hydrazines / Q000138:chemical synthesis* / Q000737:chemistry; D057927:Hydrophobic and Hydrophilic Interactions; D007700:Kinetics; D008958:Models, Molecular; D008968:Molecular Conformation; D009154:Mutation; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000737:chemistry; D010434:Pepsin A / Q000037:antagonists & inhibitors / Q000737:chemistry; D057786:Peptidomimetics / Q000138:chemical synthesis* / Q000737:chemistry; D055503:Protein Multimerization; D012083:Renin / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D000092502:Renin Inhibitors
D016333:HIV Protease; D017320:HIV Protease Inhibitors; D006834:Hydrazines; D009281:Naphthalenes; D010434:Pepsin A; D057786:Peptidomimetics; D012083:Renin; D000092502:Renin Inhibitors; C514803:p16 protease, Human immunodeficiency virus 1