Computational Design of New Cyclic Urea Inhibitors for Improved Binding of HIV-1 Aspartic Protease

2000 ◽  
Vol 268 (2) ◽  
pp. 384-389 ◽  
Author(s):  
Bhanuprakash Kotamarthi ◽  
Irena Bonin ◽  
Fabio Benedetti ◽  
Stanislav Miertus
Keyword(s):  
Computational Design ◽  
Aspartic Protease ◽  
Hiv 1

Computational Design of Centralized HIV-1 Genes

2010 ◽  
Vol 8 (8) ◽  
pp. 613-621 ◽  
Author(s):  
Miguel Arenas ◽  
David Posada
Keyword(s):  
Computational Design ◽  
Hiv 1

scholarly journals Long antibody HCDR3s from HIV-naïve donors presented on a PG9 neutralizing antibody background mediate HIV neutralization

2016 ◽  
Vol 113 (16) ◽  
pp. 4446-4451 ◽  
Author(s):  
Jordan R. Willis ◽  
Jessica A. Finn ◽  
Bryan Briney ◽  
Gopal Sapparapu ◽  
Vidisha Singh ◽  
...  
Keyword(s):  
Amino Acid ◽  
Neutralizing Antibodies ◽  
Neutralizing Antibody ◽  
Computational Design ◽  
Cell Repertoire ◽  
B Cell Repertoire ◽  
Amino Acid Length ◽  
Massive Scale ◽  
Amino Acid Mutations ◽  
Hiv 1

Development of broadly neutralizing antibodies (bnAbs) against HIV-1 usually requires prolonged infection and induction of Abs with unusual features, such as long heavy-chain complementarity-determining region 3 (HCDR3) loops. Here we sought to determine whether the repertoires of HIV-1–naïve individuals contain Abs with long HCDR3 loops that could mediate HIV-1 neutralization. We interrogated at massive scale the structural properties of long Ab HCDR3 loops in HIV-1–naïve donors, searching for structured HCDR3s similar to those of the HIV-1 bnAb PG9. We determined the nucleotide sequences encoding 2.3 × 107unique HCDR3 amino acid regions from 70 different HIV-1–naïve donors. Of the 26,917 HCDR3 loops with 30-amino acid length identified, we tested 30 for further study that were predicted to have PG9-like structure when chimerized onto PG9. Three of these 30 PG9 chimeras bound to the HIV-1 gp120 monomer, and two were neutralizing. In addition, we found 14 naturally occurring HCDR3 sequences that acquired the ability to bind to the HIV-1 gp120 monomer when adding 2- to 7-amino acid mutations via computational design. Of those 14 designed Abs, 8 neutralized HIV-1, with IC50values ranging from 0.7 to 98 µg/mL. These data suggest that the repertoire of HIV-1–naïve individuals contains rare B cells that encode HCDR3 loops that bind or neutralize HIV-1 when presented on a PG9 background with relatively few or no additional mutations. Long HCDR3 sequences are present in the HIV-naïve B-cell repertoire, suggesting that this class of bnAbs is a favorable target for rationally designed preventative vaccine efforts.

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