Multi-Functional Anti-HIV Agents Based on Amino Acid Sequences Present in Serpin C-Terminal Peptides

The observation that proteinases located at the surface of HIV-1 target cells were involved in viral infection led to the discovery of the anti-HIV-1 properties of serpin A1(α1-proteinase inhibitor, α1-antitrypsin). Antiviral activity could be explained by the capacity of serpin A1 to prevent binding of the HIV envelope glycoprotein to proteinases associated with host cell membranes. Surprisingly, serpin A1 inhibited as well HIV-1 replication and promoter activity. A1- C36, the C-terminal peptide produced after serpin-proteinase complex formation [A1(359-394)] is probably responsible for this intracellular anti-HIV activity because the synthetic, truncated 26-residue peptide A1-C26 [A1(369-394)] , comprising the complete β-hairpin structure of A1-C36, strongly inhibited HIV-1 expression in infected cells. The major receptor involved in internalization of A1-C36 and many serpin-proteinase complexes is CD91, a protein highly expressed in HIV-1-infected true non-progressors. CD91 also internalizes the antiviral defensins, structurally similar to A1-C26. A1- C26 contains a putative internalization signal pentapeptide FVFLM [A1(372-376)]. Synthetic peptides based on this sequence go to the nucleus few minutes after cell membrane interaction. VIRIP (serpin A1(353-372), virus-inhibitory peptide) is a serpin A1 fragment isolated from hemofiltrates of patients with chronic kidney failure. VIRIP does not have the complete internalization sequence and does not affect HIV-1 promoter activity but effectively blocks HIV-1 entry by binding to the fusion peptide of gp41, a crucial component of the HIV envelope glycoprotein complex. C-terminal peptides derived from serpins B9 (anti-granzyme B) and C1 (antithrombin III) were not as active as A1-C26. However, other C-terminal peptides of the more than 500 members of the serpin superfamily could be potential anti-infective agents.