title: Mechanism of HIV-1 Resistance to Short-Peptide Fusion Inhibitors Targeting the Gp41 Pocket.
abstract: The deep hydrophobic pocket on the N trimer of HIV-1 gp41 has been considered an ideal drug target. On the basis of the M-T hook structure, we recently developed short-peptide-based HIV-1 fusion inhibitors (MTSC22 and HP23), which mainly target the pocket site and possess highly potent antiviral activity. In this study, we focused on investigating their resistance pathways and mechanisms by escape HIV-1 mutants to SC22EK, a template peptide for MTSC22 and HP23. Two substitutions, E49K and N126K, located, respectively, at the N- and C-heptad repeat regions of gp41, were identified as conferring high resistance to the inhibitors targeting the pocket and cross-resistance to enfuvirtide (T20) and sifuvirtide (SFT). The underlying mechanisms of SC22EK-induced resistance include the following: (i) significantly reduced binding affinity of the inhibitors, (ii) dramatically enhanced interaction of the viral six-helix bundle, and (iii)severely damaged functionality of the viral Env complex. Our data have provided important information for the structure-function relationship of gp41 and the structure-activity relationship of viral fusion inhibitors.
  
  
  OBJECTIVE
  Enfuvirtide (T20) is the only HIV-1 fusion inhibitor in clinical use, but the problem of resistance significantly limits its use, calling for new strategies or concepts to develop next-generation drugs. On the basis of the M-T hook structure, short-peptide HIV-1 fusion inhibitors specifically targeting the gp41 pocket site exhibit high binding and antiviral activities. Here, we investigated the molecular pathway of HIV-1 resistance to the short inhibitors by selecting and mapping the escape mutants. The key substitutions for resistance and the underlying mechanisms have been finely characterized. The data provide important information for the structure-function relationship of gp41 and its inhibitors and will definitely help our future development of novel drugs that block gp41-dependent fusion.
authors: Institute of Pathogen Biology and AIDS Research Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors: Yang
authors: Y
authors: Su
authors: Institute of Pathogen Biology and AIDS Research Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors: Huihiui
authors: H
authors: Chong
authors: Institute of Pathogen Biology and AIDS Research Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors: Zonglin
authors: Z
authors: Qiu
authors: Institute of Pathogen Biology and AIDS Research Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors: Shengwen
authors: S
authors: Xiong
authors: Institute of Pathogen Biology and AIDS Research Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China yhe@ipb.pumc.edu.cn.
authors: Yuxian
authors: Y
authors: He
mesh_terms: D019943:Amino Acid Substitution; D024882:Drug Resistance, Viral; D000077560:Enfuvirtide; D015700:HIV Envelope Protein gp41 / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D023581:HIV Fusion Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects*; D009154:Mutation; D020125:Mutation, Missense; D010446:Peptide Fragments / Q000494:pharmacology*; D010455:Peptides / Q000494:pharmacology*; D011485:Protein Binding
chemical_list: D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D010446:Peptide Fragments; D010455:Peptides; C514787:gp41 protein, Human immunodeficiency virus 1; D000077560:Enfuvirtide; C505768:sifuvirtide