Debio-025 is a synthetic
cyclosporine with no immunosuppressive capacity but a high inhibitory potency against
cyclophilin A (CypA)-associated cis-trans
prolyl isomerase (
PPIase) activity. A lack of immunosuppressive effects compared to that of
cyclosporine was demonstrated both in vitro and in vivo. For three
cyclosporines, the inhibitory potential against
PPIase activity was quantitatively correlated with that against human immunodeficiency virus type 1 (HIV-1) replication.
Debio-025 selectively inhibited the replication of HIV-1 in a CD4+ cell line and in peripheral blood mononuclear cells: potent activity was demonstrated against clinical isolates of various HIV-1 subtypes, including isolates with multidrug resistance to
reverse transcriptase and
protease inhibitors. Simian immunodeficiency virus and HIV-2 strains were generally resistant to inhibition by Debio-025; however, some notable exceptions of sensitive HIV-2 clinical isolates were detected. In two-
drug combination studies, additive inhibitory effects were found between
Debio-025 and 19 clinically used drugs of different classes. Clinical HIV-1 isolates that are naturally resistant to
Debio-025 and that do not depend on CypA for
infection were identified. Comparison of the amino acid sequences of the CypA binding domain of the capsid (CA)
protein from Debio-025-sensitive and -resistant HIV-1 isolates indicated that resistance was mostly associated with an H87Q/P exchange. Mechanistically,
cyclosporines competitively inhibit the binding of CypA to the HIV-1 CA
protein, which is an essential interaction required for early steps in HIV-1 replication. By real-time PCR we demonstrated that early reverse transcription is reduced in the presence of
Debio-025 and that late reverse transcription is almost completely blocked. Thus,
Debio-025 seems to interfere with the function of CypA during the progression/completion of HIV-1 reverse transcription.