GSK3532795(前身为BMS955176)是第二代成熟抑制剂(MI),已通过2b期研究用于治疗HIV-1感染。通过体外方法评估了对GSK3532795的抗性发展,并与在HIV-1感染参与者的2a期概念验证研究中获得的信息相关。低浓度和高浓度的GSK3532795均用于体外选择,并降低对GSK3532795的敏感性,特异性定位在衣壳/间隔肽1(SP1)连接附近的氨基酸,其切割被MIs阻断。两个关键替换,A364V或V362I,被选中,后者需要二级替换以降低对GSK3532795的易感性。观察到三种主要类型的二级取代,其中没有一个单独降低GSK3532795敏感性。第一种类型是在衣壳C端结构域和下游SP1区(包括(Gag编号)R286K,A326T,T332S/N,I333V和V370A/M)。第二个,是与V362I一起发生的病毒蛋白酶中的R41G取代。第三个是在衣壳N端结构域,在亲环蛋白A结合域内(V218A/M,H219Q和G221E)。H219Q增加了病毒复制能力并降低了生长不良的病毒的易感性。在2a期研究中,在HIV-1感染的参与者中,在基线时也观察到了这些替代的一个子集,其中一些是在GSK35323795治疗后选择的.
GSK3532795 (formerly BMS955176) is a second-generation maturation inhibitor (MI) that progressed through a Phase 2b
study for treatment of HIV-1 infection. Resistance development to GSK3532795 was evaluated through in vitro methods and was correlated with information obtained in a Phase 2a proof-of-concept
study in HIV-1 infected participants. Both low and high concentrations of GSK3532795 were used for selections in vitro, and reduced susceptibility to GSK3532795 mapped specifically to amino acids near the capsid/ spacer peptide 1 (SP1) junction, the cleavage of which is blocked by MIs. Two key substitutions, A364V or V362I, were selected, the latter requiring secondary substitutions to reduce susceptibility to GSK3532795. Three main types of secondary substitutions were observed, none of which reduced GSK3532795 susceptibility in isolation. The first type was in the capsid C-terminal domain and downstream SP1 region (including (Gag numbering) R286K, A326T, T332S/N, I333V and V370A/M). The second, was an R41G substitution in viral protease that occurred with V362I. The third was seen in the capsid N-terminal domain, within the cyclophilin A binding domain (V218A/M, H219Q and G221E). H219Q increased viral replication capacity and reduced susceptibility of poorly growing viruses. In the Phase 2a
study, a subset of these substitutions was also observed at baseline and some were selected following GSK35323795 treatment in HIV-1-infected participants.