title: Discovery of entry inhibitors for HIV-1 via a new de novo protein design framework.
abstract: A new (to our knowledge) de novo design framework with a ranking metric based on approximate binding affinity calculations is introduced and applied to the discovery of what we believe are novel HIV-1 entry inhibitors. The framework consists of two stages: a sequence selection stage and a validation stage. The sequence selection stage produces a rank-ordered list of amino-acid sequences by solving an integer programming sequence selection model. The validation stage consists of fold specificity and approximate binding affinity calculations. The designed peptidic inhibitors are 12-amino-acids-long and target the hydrophobic core of gp41. A number of the best-predicted sequences were synthesized and their inhibition of HIV-1 was tested in cell culture. All peptides examined showed inhibitory activity when compared with no drug present, and the novel peptide sequences outperformed the native template sequence used for the design. The best sequence showed micromolar inhibition, which is a 3-15-fold improvement over the native sequence, depending on the donor. In addition, the best sequence equally inhibited wild-type and Enfuvirtide-resistant virus strains.
authors.affiliation: Department of Chemical and Biological Engineering, Princeton University, Princeton, NJ, USA.
authors.forename: M L
authors.initials: ML
authors.lastname: Bellows
authors.forename: M S
authors.initials: MS
authors.lastname: Taylor
authors.forename: P A
authors.initials: PA
authors.lastname: Cole
authors.forename: L
authors.initials: L
authors.lastname: Shen
authors.forename: R F
authors.initials: RF
authors.lastname: Siliciano
authors.forename: H K
authors.initials: HK
authors.lastname: Fung
authors.forename: C A
authors.initials: CA
authors.lastname: Floudas
mesh_terms: D000595:Amino Acid Sequence; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000821:virology; D018360:Crystallography, X-Ray; D055808:Drug Discovery; D000077560:Enfuvirtide; D057809:HEK293 Cells; D015700:HIV Envelope Protein gp41 / Q000737:chemistry / Q000494:pharmacology; D023581:HIV Fusion Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000302:isolation & purification; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions / Q000187:drug effects; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology; D010455:Peptides / Q000737:chemistry; D015202:Protein Engineering / Q000379:methods*; D053586:Virus Internalization / Q000187:drug effects*
chemical_list: D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D050505:Mutant Proteins; D010446:Peptide Fragments; D010455:Peptides; D000077560:Enfuvirtide