The use of synthetic peptides as HIV-1 inhibitors has been the object of research over recent years. A large
number of peptides that affect different stages of the HIV-1 life cycle have been and continue to be studied due to their
possible clinical application in the fight against HIV-1 infection. The main advantages of synthetic peptides as therapeutic
agents are their low systemic toxicity, the fact that structural modifications can be made to them and their resulting capacity
to mimic certain substrates or epitopes.
HIV-1-inhibiting peptides have been identified and/or developed using different methods. Some therapeutic peptides such
as enfuvirtide—already approved for clinical use—are derived from HIV-1 itself. Others are natural peptides such as
chemokines, defensins or the “virus inhibitory peptide”; while still others have been designed and synthesized based on
crystallographic data on HIV-1 proteins or from peptide libraries.
Initial attempts at therapeutic applications focused on HIV-coded enzymes (reverse transcriptase, protease and, more recently,
integrase). However, structural HIV proteins and, more specifically, the mechanisms that involve the virus in cell
infection and replication are now also considered therapeutic targets. Several chemical strategies to improve both the stability
of peptides and their pharmacokinetics, including prolonging their half-life, have recently been described in the literature.
There is growing an interest in inhibitors that prevent HIV entry into the host cell (fusion inhibitors) which could lead to
the development of new antiviral agents. Knowledge of the mechanism of action of fusion inhibitors is essential not only
for the development of future generations of entry inhibitors, but also to gain an understanding of the form and kinetics of
membrane fusion induced by the virus. The physico-chemical processes involved at the interface between the lipid surface
of cells and enveloped viruses (such as HIV-1) are essential to the action of peptides that prevent HIV-1 entry into the
host cell. The interaction of these peptides with biological membranes may be related to their inhibition efficiency and to
their mechanism of action, as the HIV-1 gp41 glycoprotein is bound and confined between the cellular membrane and the