Targeting a binding pocket within the trimer-of-hairpins: small-molecule inhibition of viral fusion.
Trimeric class I virus fusion proteins undergo a series of conformational rearrangements that leads to the association of C- and N-terminal heptad repeat domains in a "trimer-of-hairpins" structure, facilitating the apposition of viral and cellular membranes during fusion. This final fusion hairpin structure is sustained by protein-protein interactions, associations thought initially to be refractory to small-molecule inhibition because of the large surface area involved. By using a photoaffinity analog of a potent respiratory syncytial virus fusion inhibitor, we directly probed the interaction of the inhibitor with its fusion protein target. Studies have shown that these inhibitors bind within a hydrophobic cavity formed on the surface of the N-terminal heptad-repeat trimer. In the fusogenic state, this pocket is occupied by key amino acid residues from the C-terminal heptad repeat that stabilize the trimer-of-hairpins structure. The results indicate that a low-molecular-weight fusion inhibitor can interfere with the formation or consolidation of key structures within the hairpin moiety that are essential for membrane fusion. Because analogous cavities are present in many class I viruses, including HIV, these results demonstrate the feasibility of this approach as a strategy for drug discovery.
Cianci
Christopher
C
Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, CT 06492, USA.
Langley
David R
DR
Dischino
Douglas D
DD
Sun
Yaxiong
Y
Yu
Kuo-Long
KL
Stanley
Anne
A
Roach
Julia
J
Li
Zhufang
Z
Dalterio
Richard
R
Colonno
Richard
R
Meanwell
Nicholas A
NA
Krystal
Mark
M
D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000494:pharmacology; D001562:Benzimidazoles / Q000494:pharmacology; D001665:Binding Sites; D008561:Membrane Fusion / Q000187:drug effects* / Q000502:physiology*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019920:Photoaffinity Labels; D011487:Protein Conformation; D012136:Respiratory Syncytial Viruses / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D014760:Viral Fusion Proteins / Q000737:chemistry* / Q000235:genetics / Q000502:physiology*
D000998:Antiviral Agents; C482453:BMS 433771; D001562:Benzimidazoles; D019920:Photoaffinity Labels; D014760:Viral Fusion Proteins