KuINins as a New Class of HIV-1 Inhibitors That Block Post-Integration DNA Repair

Abstract

Integration of HIV-1 genomic cDNA results in the formation of single-strand breaks in cellular DNA, which must be repaired for efficient viral replication. Post-integration DNA repair mainly depends on the formation of the HIV-1 integrase complex with the Ku70 protein, which promotes DNA-PK assembly at sites of integration and its activation. Here, we have developed a first-class inhibitor of the integrase-Ku70 complex formation that inhibits HIV-1 replication in cell culture by acting at the stage of post-integration DNA repair. This inhibitor, named s17, does not affect the main cellular function of Ku70, namely its participation in the repair of double-strand DNA breaks through the non-homologous end-joining pathway. Using a molecular dynamics approach, we have constructed a model for the interaction of s17 with Ku70. According to this model, the interaction of two phenyl radicals of s17 with the L76 residue of Ku70 is important for this interaction. The requirement of two phenyl radicals in the structure of s17 for its inhibitory properties was confirmed using a set of s17 derivatives. We propose to stimulate compounds that inhibit post-integration repair by disrupting the integrase binding to Ku70 KuINins.

Brief Histories of Retroviral Integration Research and Associated International Conferences

“…Additional cellular proteins since implicated in the repair of the HIV-1 integration intermediate include Ku70 [ 133 ], Ataxia-telangiectasia mutated (ATM) kinase, DNA-dependent protein kinase (DNA-PK) [ 134 ], and Fanconi anemia factors FANCI and FANCD2 [ 135 ]. Understanding the molecular details of DNA repair of the HIV-1 integration intermediate may provide new approaches to antiretroviral therapy [ 136 ].…”

Synthesis of Spiro[imidazole‐4,3′‐pyrrolo[1,2‐a]quinolin]‐ 5‐ones via 1,3‐Dipolar Cycloaddition of Quinolinium Ylides with Arylydeneimidazol‐4‐ones

“…[18][19][20][21] Only recently, after seminal works [22,23] on the in situ elaboration of the cycloadducts into bioactive aromatized or rearranged products, the research interest into reactions of aromatic azomethine ylides have revived. [24][25][26][27][28][29][30][31][32][33][34] Recently, we have discovered that cycloaddition products A, derived from quinoline ylides and arylidenecyanocinnamic amides, are potent inhibitors of HIV-1 integrase (Scheme 1, b) [35] However, derivatives such as A appeared to have limited stability. At the same time we have demonstrated that arylideneimidazolones are able to react with unstabilized azomethine ylides.…”