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Description

A cell-permeable diphenylpyrazolo compound that is shown to disrupt HIV accessary protein Nef dimerization (IC50 = 3 µ,M in HEK293T cells) and prevent Nef-mediated Src family kinase (SFK) Hck activation (IC50 = 2.8 µ,M) without directly affecting the catalytic activity of c-Src, Hck, Lck, or Lyn (IC50 >20 µ,M). Shown to effectively suppress HIV and SIV viral replication (IC50<0.3 µ,M in 9 d HIV-1 NL4-3-infected CEM-T4 cultures, IC50 = 1 µ,M in 5 d SIV DeltaB670-infected CEM-174 cultures) and infectivity (45% and 50% inhibition against HIV-1 NL4-3 and SIV DeltaB670, respectively, following 48 h 3 µ,M B9 treatment in TZM-bl reporter cells) in a Nef-dependent manner, being ineffective against the replication of Nef-defective HIV-1 mutant. Molecular docking studies predict a high-affinity B9-targeting site formed at the Nef dimerization interface and a low-affinity B9-binding site on each Nef monomer at the dimer interface periphery, with Asn126 contributing to both modes of binding. Consistently, in vitro binding studies reveal two B9 KD values of 1.72 nM and 860 nM toward full-length HIV-1 Nef and a complete loss of B9 binding toward Nef N126A/L/Q mutants., A cell-permeable diphenylpyrazolo compound that disrupts HIV accessary protein Nef dimerization (IC50 = 3 µ,M in HEK293T cells) and prevents Nef-mediated Src family kinase Hck activation (IC50 = 2.8 µ,M) without directly affecting the catalytic activity of c-Src, Hck, Lck, or Lyn. Shown to suppress HIV and SIV viral replication (IC50/strain/culture = 1 µ,M/SIV DeltaB670/CEM-174 and <0.3 µ,M/HIV-1 NL4-3/CEM-T4) and infectivity, being ineffective against the replication of Nef-defective HIV-1 mutant. Molecular docking and in vitro binding studies reveal a high-affinity B9-targeting site formed at the Nef dimerization interface and a low-affinity binding site on each Nef monomer at the dimer interface periphery.