Non Protein TherapeuticsHIV-derived peptide mimics
Section editor:
Peter Timmerman – Pepscan Therapeutics B.V., P.O. Box 2098, 8203 AB Lelystad, The Netherlands
Introduction
According to the UNAIDS 2008 Report on the global AIDS epidemic (http://www.unaids.org/en/KnowledgeCentre/HIVData/GlobalReport/2008/2008_Global_report.asp), more than 33 million people worldwide are infected with the human immune deficiency virus (HIV), the causative agent of the acquired immune deficiency syndrome (AIDS), in 2007, and an estimated 2 million people died from AIDS. The inherent ability of HIV to escape the host immune response, as well its high genetic variability, which is caused by the unusually high error rate of the HIV reverse transcriptase (RT) [1], has greatly hampered the sustained development of therapeutic and preventive drugs. At present, no cure is available for the disease, nor is an effective protective HIV vaccine.
Entry of HIV into its host cell, as well as its replication, is mediated by a range of specific interactions between viral and host cell proteins. Peptides mimicking the binding sites of the proteins involved in these interactions are not only valuable tools to explore the respective interactions at the molecular level, but also candidates for therapeutic intervention through specific inhibition of these interactions. The structural (Gag, Pol and Env), regulatory (Tat and Rev) and accessory (Nef, Vif, Vpu and Vpr) proteins encoded by the RNA of HIV (Fig. 1) have been the target for the design of peptides that mimic their binding and functional properties [2].
In general, synthetic peptides can be considered excellent tools for the mimicry of specific protein sites, because they can be generated as exact copies of protein fragments, as well as in diverse chemical modifications, which includes the incorporation of a large range of nonproteinogenic amino acids, as well as the modification of the peptide backbone. Apart from extending the chemical and structural diversity presented by peptides, such modifications also increase the proteolytic stability of the molecules, enhancing their potential as drug candidates.
Section snippets
Strategy 1: peptides mimicking Env proteins
The ability of HIV to enter its host cell is located in its envelope protein (Env) on the surface of the virus. Env forms trimeric spikes and consists of two glycoproteins (gp120 and gp41).
The initial event in the HIV entry process is the interaction of gp120 with the N-terminal extracellular domain of the host receptor CD4 (Fig. 2). The CD4 binding site (CD4bs) of gp120 represents a conserved region in this otherwise highly variable protein, as it is required to maintain virus infectivity.
Strategy 2: peptides mimicking Pol proteins
The polyprotein encoded by the pol gene (Entrez GeneID: 155348) is post-translationally cleaved into four enzymes RT, protease, RNAse and integrase. Inhibitors of these enzymes are components of drug cocktails used in standard anti-retroviral therapy. Most of these enzyme inhibitors are not peptides, but smaller molecules that mimic the substrates of the respective enzymes, thus blocking their active sites.
Nevertheless, peptide mimics of Pol proteins have also been reported, including peptides
Strategy 3: peptides mimicking Gag proteins
The protein encoded by the gag gene (GeneID: 155348) is proteolytically processed to yield the matrix, nucleocapsid and capsid proteins, as well as p6. The correct assembly of these proteins is crucial for the formation of mature capsids. Consequently, inhibition of Gag proteins is likely to slow down virus replication.
A range of peptides involved in the inhibition of viral replication have been identified [2], many of them derived from Gag proteins. A peptide presenting residues 169–191 of the
Strategy 4: peptides mimicking accessory proteins
In addition to the structural and regulatory proteins discussed above, the HIV genome also encodes four accessory proteins (Nef, Vif, Vpu, Vpr). During viral replication, these proteins alter cellular pathways via multiple interactions with host cell proteins. Inhibiting these interactions is a promising strategy to inhibit HIV replication.
Peptides derived from Env and Nef, respectively, have been used to enhance mucosal and systemic immune responses against HIV [44].
Two peptides derived from
Strategy 5: peptides mimicking Tat proteins
The gene tat (GeneID: 155871) encodes for a transactivator protein which binds to a region (TAR) on newly synthesized viral RNA. On the basis of the solution structure of Tat, cyclic peptides were synthesized which functionally mimic the Tat arginine-rich motif. They were tested for their ability to facilitate nuclear localization of peptide conjugates with bovine serum albumin (BSA). It was shown that these peptides hindered Tat-NLS-BSA to enter the nucleus in vitro. Additionally, the peptides
Conclusion
Over the past decades, peptides that structurally and/or functionally mimic HIV proteins have significantly contributed to the molecular and structural understanding of HIV live cycle and infection pathways (Table 1). Moreover, such peptides are promising candidates for therapeutic and preventive anti-HIV strategies, because they can be used as inhibitors of virus–host interactions that are essential for virus entry and replication. Furthermore, peptides that mimic the binding sites of HIV
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