IN-VITRO ANTI-HUMAN-IMMUNODEFICIENCY-VIRUS (HIV) ACTIVITY OF XM323, ANOVEL HIV PROTEASE INHIBITOR

XM323 represents a novel class of potent inhibitors of human immunodef iciency virus (HIV) protease. In vitro studies have shown that inhibit ion of this enzyme translates into potent inhibition of replication of HIV type 1 (HIV-1) and HIV-2. The inhibition of virus replication was assessed with three assays designed to measure the production of infe ctious virus, viral RNA, or p24 antigen. The production of mature infe ctious virions was measured with a yield reduction assay. By this assa y, several strains and isolates of HIV-1 and HIV-2 were shown to be su sceptible to XM323 in two lymphoid cell lines (MT-2 and H9) and in nor mal peripheral blood mononuclear cells, with a concentration required for 90% inhibition (IC90) of 0.12 +/- 0.04 mu M (mean +/- standard dev iation). The production of HIV-1(RF) RNA was measured with an RNA hybr idization-caputure assay. With this assay, XM323 was shown to be a pot ent inhibitor of HIV-1(RF) replication, with an IC90 of 0.063 +/- 0.03 2 mu M. A third measure of virus replication, the production of p24 vi ral antigen, an essential protein component of the virion, was determi ned with the AIDS Clinical Trial Group-Department of Defense periphera l blood mononuclear cell consensus assay. This assay was used for expa nded testing of XM323 against 28 clinical isolates and laboratory stra ins of HIV-1. XM323 was shown to be equally effective against zidovudi ne-susceptible and zidovudine-resistant isolates of HIV-1, with an ove rall IC90 of 0.16 +/- 0.06 mu M.