title: Small-molecule HIV-1 entry inhibitors targeting gp120 and gp41: a patent review (2010-2015).
abstract: It is essential to discover and develop small-molecule HIV-1 entry inhibitors with suitable pharmaceutical properties. Areas covered: We review the development of small-molecule HIV-1 entry inhibitors as evidenced in patents, patent applications, and related research articles published between 2010 and 2015. Expert opinion: HIV-1 Env gp120 and gp41 are important targets for development of HIV-1 entry inhibitors. The Phe43 pocket in gp120 and the highly conserved hydrophobic pocket on gp41 NHR-trimer are important targets for identification of HIV-1 attachment and fusion inhibitors, respectively. Compounds that bind to Phe43 pocket can block viral gp120 binding to CD4 on T cells, thus inhibiting HIV-1 attachment. However, most compounds targeting Phe43 pocket identified so far are HIV-1 entry agonists with the ability to enhance infectivity of HIV-1 in CD4-negative cells. Therefore, it is essential to identify HIV-1 entry antagonist-based HIV-1 attachment/entry inhibitors. Compounds binding to the gp41 hydrophobic pocket may inhibit CHR binding to the gp41 NHR trimer, thus blocking six-helix bundle formation and gp41-mediated virus-cell fusion. However, most lead compounds targeting this pocket have low potency, possibly because the pocket is too big or too deep. Therefore, it is necessary to identify other pockets in gp41 for developing HIV-1 fusion/entry inhibitors.
authors.affiliation: a Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, School of Basic Medical Science , Fudan University , Shanghai , China.
authors.forename: Wen
authors.initials: W
authors.lastname: Li
authors.affiliation: a Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, School of Basic Medical Science , Fudan University , Shanghai , China.
authors.forename: Lu
authors.initials: L
authors.lastname: Lu
authors.affiliation: b Key Laboratory of Reproduction Regulation of NPFPC, SIPPR, IRD , Fudan University , Shanghai , China.
authors.forename: Weihua
authors.initials: W
authors.lastname: Li
authors.affiliation: a Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, School of Basic Medical Science , Fudan University , Shanghai , China.|b Key Laboratory of Reproduction Regulation of NPFPC, SIPPR, IRD , Fudan University , Shanghai , China.|c Lindsley F. Kimball Research Institute , New York Blood Center , New York , NY , USA.
authors.forename: Shibo
authors.initials: S
authors.lastname: Jiang
mesh_terms: D015195:Drug Design; D015699:HIV Envelope Protein gp120 / Q000378:metabolism; D015700:HIV Envelope Protein gp41 / Q000378:metabolism; D023581:HIV Fusion Inhibitors / Q000494:pharmacology*; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D010330:Patents as Topic
chemical_list: D015699:HIV Envelope Protein gp120; D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors
keywords: C-terminal heptad repeat (CHR); HIV-1; N-terminal heptad repeat (NHR); entry inhibitor; gp120; gp41; small-molecule