Covalent fusion inhibitors targeting HIV-1 gp41 deep pocket

Abstract

Covalent inhibitors form covalent adducts with their target, thus permanently inhibiting a physiological process. Peptide fusion inhibitors, such as T20 (Fuzeon, enfuvirtide) and C34, interact with the N-terminal heptad repeat of human immunodeficiency virus type 1 (HIV-1) gp41 glycoprotein to form an inactive hetero six-helix bundle (6-HB) to prevent HIV-1 infection of host cells. A covalent strategy was applied to peptide fusion inhibitor design by introducing a thioester group into C34-like peptide. The modified peptide maintains the specific interaction with its target N36. After the 6-HB formation, a covalent bond between C- and N-peptides was formed by an inter-helical acyl transfer reaction, as characterized by various biophysical and biochemical methods. The covalent reaction between the reactive C-peptide fusion inhibitor and its N-peptide target is highly selective, and the reaction greatly increases the thermostability of the 6-HB. The modified peptide maintains high potency against HIV-1-mediated cell-cell fusion and infection.

Inhibition of HIV Entry by Targeting the Envelope Transmembrane Subunit gp41

“…A thioester was placed onto C34 in order to initiate an acyl transfer reaction. This is projected to be a better mimic of what is happening under physiological conditions when polypeptides are synthesized [95, 96]. In the process of nonribosomal peptide synthesis, a peptide bond is formed between a carboxy-thioester of the upstream substrate and a free amine on a downstream amino acid by 4’ phosphopantetheinyl cofactor (reviewed in [97]).…”

“…In the process of nonribosomal peptide synthesis, a peptide bond is formed between a carboxy-thioester of the upstream substrate and a free amine on a downstream amino acid by 4’ phosphopantetheinyl cofactor (reviewed in [97]). This acyl transfer reaction is able to form a covalent bond between the modified C34 and the NHR resulting in high potency anti-HIV activity, which correlated to increased thermostability of 6HB when studied in vitro [95, 96]. …”

Covalent Inhibition of HIV‐1 Integrase by N‐Succinimidyl Peptides

“…[12][13][14][15][16][17] For example, covalent fusion inhibitors of HIV-1g p41 protein, which bind via thioester or maleimide groups, werer eported. [18][19][20] Most of the covalenti nhibitors reported so far are small molecules [1][2][3][4][5][6][12][13][14][15][16][17] that use electrophilic moieties (e.g., a,b-unsaturated ketone, ahaloketone, cyanamide or fluorophosphonate) to bind the target protein. However,s uch compoundsp ossess potential toxicitya nd immunogenicity mediated by nonspecific offtarget reactions with nucleophiless uch as glutathionea nd proteins with active cysteiner esiduess uch as proteases.…”

“…Covalent inhibition has the potential to overcome toxicological disadvantages of noncovalent inhibitors . For example, covalent fusion inhibitors of HIV‐1 gp41 protein, which bind via thioester or maleimide groups, were reported . Most of the covalent inhibitors reported so far are small molecules that use electrophilic moieties (e.g., α,β‐unsaturated ketone, α‐haloketone, cyanamide or fluorophosphonate) to bind the target protein.…”

The impact of antibodies to human glycoprotein CD4 and gamma-interferon on the t-cell immunity and the cytokine levels in patients co-infected with HIV/HCV during the antiretroviral therapy

“…Эти макромолекулы, экспрессируемые на поверхности Т-лимфоцитов, макрофагов, а также микроглии и дендритных клеток [5], необходимы для проникновения ВИЧ в клетку. При взаимодействии и связывании вириона с гликопротеином CD4 на мембране CD4+ клетки, конформация вирусного гликопротеина gp120 изменяется, и концевые участки трансмембранного гликопротеина gp41 проникают в плазматическую мембрану клетки, инициируя слияние вириона с клеткой-хозяином [6]. В то же время, широкого внедрения препаратов, блокирующих CD4-рецепторы или его корецепторы, пока не произошло: на сегодняшний день из данной группы доступен только маравирок [3].…”