Small-molecule HIV-1 entry inhibitors targeting gp120 and gp41: a patent review (2010-2015)

ABSTRACT

Introduction: 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.

KEYWORDS:

• HIV-1
• gp120
• gp41
• small-molecule
• entry inhibitor
• C-terminal heptad repeat (CHR)
• N-terminal heptad repeat (NHR)

Article highlights

• The clinical applications of peptide-based HIV-1 entry inhibitors are limited by the lack of oral bioavailability and easy degradation after injection.

• The Phe43 pocket on gp120 is a critical target for identification of HIV-1 entry antagonist-based HIV-1 attachment/entry inhibitors.

• Other relative conserved regions in gp120, such as the β20-β21 strands, can also serve as targets for identification of HIV-1 attachment/entry inhibitors.

• The highly conserved hydrophobic pocket on gp41 NHR trimer is important target for development of novel small-molecule HIV-1 fusion/entry inhibitors.

• Other target sites in or along the groove on the gp41 NHR trimers should also be identified for screening novel small-molecule HIV-1 fusion/entry inhibitors.

• Emerging nanomaterials offer promising drug-delivery platforms for HIV-1 entry inhibitors with expanded half-lives and improved pharmacokinetics profiles.

This box summarizes the key points contained in the article.

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

The authors were supported by grants from the National Science Foundation of China (81361120378 to S Jiang and 81373456 to L Lu) and the National 863 Program of China (2015AA020930 to L Lu).