Effects of L-and D-REKR amino acid-containing peptides on HIV and SIV envelope glycoprotein precursor maturation and HIV and SIV replication

Bouchaib Bahbouhi (1) , Nathalie Chazal (2) , Nabil Georges Seidah , Cristina Chiva (3) , Marcelo Kogan (3) , Fernando Albericio (3) , Ernest Giralt (3) , Elmostafa Bahraoui (1)

1 Immunologie-Virologie
2 IRIM - Institut de Recherche en Infectiologie de Montpellier
3 University of Barcelona

The aim of the present study was to evaluate the capacity of synthetic l- and d-peptides encompassing the HIV-1(BRU) gp160 REKR cleavage site to interfere with HIV and simian immuno-deficiency virus (SIV) replication and maturation of the envelope glycoprotein (Env) precursors. To facilitate their penetration into cells, a decanoyl (dec) group was added at the N-terminus. The sequences synthesized included dec5d or dec5l (decREKRV), dec9d or dec9l (decRVVQREKRV) and dec14d or dec14l (TKAKRRVVQREKRV). The peptide dec14d was also prepared with a chloromethane (cmk) group as C-terminus. Because l-peptides exhibit significant cytotoxicity starting at 35 microM, further characterization was conducted mostly with d-peptides, which exhibited no cytotoxicity at concentrations higher than 70 microM. The data show that only dec14d and dec14dcmk could inhibit HIV-1(BRU), HIV-2(ROD) and SIV(mac251) replication and their syncytium-inducing capacities. Whereas peptides dec5d and dec9d were inactive, dec14dcmk was at least twice as active as peptide dec14d. At the molecular level, our data show a direct correlation between anti-viral activity and the ability of the peptides to interfere with maturation of the Env precursors. Furthermore, we show that when tested in vitro the dec14d peptide inhibited PC7 with an inhibition constant K(i)=4.6 microM, whereas the peptide dec14l preferentially inhibited furin with a K(i)=28 microM. The fact that PC7 and furin are the major prohormone convertases reported to be expressed in T4 lymphocytes, the principal cell targets of HIV, suggests that they are involved in the maturation of HIV and SIV Env precursors.

Mots clés: envelope processing; prohormone convertase; serine endoprotease inhibitor; synthetic D-peptide

Domaines: Virologie

Bouchaib Bahbouhi, Nathalie Chazal, Nabil Georges Seidah, Cristina Chiva, Marcelo Kogan, et al.. Effects of L-and D-REKR amino acid-containing peptides on HIV and SIV envelope glycoprotein precursor maturation and HIV and SIV replication. Biochemical Journal, 2002, 366 (Part 3), pp.863-872. ⟨10.1042/BJ20020052⟩. ⟨hal-02147211⟩