Why are HIV-1 fusion inhibitors not effective against SARS-CoV? Biophysical evaluation of molecular interactions.
The envelope spike (S) glycoprotein of the severe acute respiratory syndrome associated coronavirus (SARS-CoV) mediates the entry of the virus into target cells. Recent studies point out to a cell entry mechanism of this virus similar to other enveloped viruses, such as HIV-1. As it happens with other viruses peptidic fusion inhibitors, SARS-CoV S protein HR2-derived peptides are potential therapeutic drugs against the virus. It is believed that HR2 peptides block the six-helix bundle formation, a key structure in the viral fusion, by interacting with the HR1 region. It is a matter of discussion if the HIV-1 gp41 HR2-derived peptide T20 (enfuvirtide) could be a possible SARS-CoV inhibitor given the similarities between the two viruses. We tested the possibility of interaction between both T20 (HIV-1 gp41 HR2-derived peptide) and T-1249 with S protein HR1- and HR2-derived peptides. Our biophysical data show a significant interaction between a SARS-CoV HR1-derived peptide and T20. However, the interaction is only moderate (K(B)=(1.1+/-0.3)x10(5) M(-1)). This finding shows that the reasoning behind the hypothesis that T20, already approved for clinical application in AIDS treatment, could inhibit the fusion of SARS-CoV with target cells is correct but the effect may not be strong enough for application.
Veiga
Salomé
S
Centro de Química e Bioquímica, Faculdade de Ciências da Universidade de Lisboa, Campo Grande C8, 1749-016 Lisboa, Portugal.
Yuan
Yunyun
Y
Li
Xuqin
X
Santos
Nuno C
NC
Liu
Gang
G
Castanho
Miguel A R B
MA
D000595:Amino Acid Sequence; D000077560:Enfuvirtide; D015700:HIV Envelope Protein gp41 / Q000494:pharmacology; D023581:HIV Fusion Inhibitors / Q000494:pharmacology*; D057927:Hydrophobic and Hydrophilic Interactions; D008081:Liposomes; D010446:Peptide Fragments / Q000494:pharmacology; D010713:Phosphatidylcholines; D045473:Severe acute respiratory syndrome-related coronavirus / Q000187:drug effects*; D014760:Viral Fusion Proteins / Q000737:chemistry
D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D008081:Liposomes; D010446:Peptide Fragments; D010713:Phosphatidylcholines; D014760:Viral Fusion Proteins; C474741:peptide T1249; D000077560:Enfuvirtide; C028694:1-palmitoyl-2-oleoylphosphatidylcholine