Design of peptide-based inhibitors for human immunodeficiency virus type 1 strains resistant to T-20.
Enfuvirtide (T-20) is a fusion inhibitor that suppresses replication of human immunodeficiency virus (HIV) variants with multi-drug resistance to reverse transcriptase and protease inhibitors. It is a peptide derived from the C-terminal heptad repeat (C-HR) of HIV-1 gp41, and it prevents interactions between the C-HR and the N-terminal HR (N-HR) of gp41, thus interfering with conformational changes that are required for viral fusion. However, prolonged therapies with T-20 result in the emergence of T-20-resistant strains that contain primary mutations such as N43D in the N-HR of gp41 (where T-20 and C-HR bind) that help the virus escape at a fitness cost. Such variants often go on to acquire a secondary mutation, S138A, in the C-HR of gp41 region that corresponds to the sequence of T-20. We demonstrate here that the role of S138A is to compensate for the impaired fusion kinetics of HIV-1s carrying primary mutations that abrogate binding of T-20. To preempt this escape strategy, we designed a modified T-20 variant containing the S138A substitution and showed that it is a potent inhibitor of both T-20-sensitive and T-20-resistant viruses. Circular dichroism analysis revealed that the S138A provided increased stability of the 6-helix bundle. We validated our approach on another fusion inhibitor, C34. In this case, we designed a variant of C34 with the secondary escape mutation N126K and showed that it can effectively inhibit replication of C34-resistant HIV-1. These results prove that it is possible to design improved peptide-based fusion inhibitors that are efficient against a major mechanism of drug resistance.
Izumi
Kazuki
K
Institute for Virus Research, Kyoto University, 53 Kawaramachi, Shogoin, Kyoto 606-8507, Japan.
Kodama
Eiichi
E
Shimura
Kazuya
K
Sakagami
Yasuko
Y
Watanabe
Kentaro
K
Ito
Saori
S
Watabe
Tsuyoshi
T
Terakawa
Yukihiro
Y
Nishikawa
Hiroki
H
Sarafianos
Stefan G
SG
Kitaura
Kazuo
K
Oishi
Shinya
S
Fujii
Nobutaka
N
Matsuoka
Masao
M
D019943:Amino Acid Substitution; D015195:Drug Design; D018432:Drug Resistance, Multiple / Q000187:drug effects* / Q000235:genetics; D024882:Drug Resistance, Viral / Q000187:drug effects* / Q000235:genetics; D000077560:Enfuvirtide; D015700:HIV Envelope Protein gp41 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D023581:HIV Fusion Inhibitors / Q000494:pharmacology*; D015658:HIV Infections / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D015497:HIV-1 / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D020125:Mutation, Missense; D010446:Peptide Fragments / Q000235:genetics / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects* / Q000235:genetics
D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D010446:Peptide Fragments; C514787:gp41 protein, Human immunodeficiency virus 1; D000077560:Enfuvirtide