374623 From HIV-1 gp120 V3 Loop Binding to CXCR4 / CCR5, to De Novo Design of a Dual Targeted CXCR4 / CCR5 Anti HIV-1 Peptide

Tuesday, November 18, 2014: 12:48 PM
205 (Hilton Atlanta)
Phanourios Tamamis, James Smadbeck and Christodoulos A. Floudas, Department of Chemical and Biological Engineering, Princeton University, Princeton, NJ

The human immunodeficiency virus (HIV) infection depletes the CD4 T cell population and eventually leads to acquired immunodeficiency syndrome (AIDS). The most critical step of HIV-1 entry to the host cell comprises the binding of envelope glycoprotein, gp120, to CD4 and a coreceptor CXCR4 [1] and/or CCR5 [2]. The molecular recognition of CXCR4 and / or CCR5 by HIV-1 is predominantly mediated by the HIV-1 gp120 V3 loop, a highly flexible fragment which exhibits large sequence variability among HIV-1 patients [1,2,3]. Maraviroc, the only FDA approved HIV-1 entry-inhibitor, selectively binds only to CCR5, and thus, it is effective only against the CCR5-tropic viruses.

We investigated the binding of a dual-tropic HIV-1 gp120 V3 loop (recognizing both CXCR4 and CCR5) in complex with CXCR4 [1] and CCR5 [2], using a comprehensive set of computational tools, predominantly based on molecular dynamics simulations and free energy calculations [1,2,4,5]. We report, what is to our knowledge, the first complete HIV-1 gp120 V3 loop : CXCR4 [1] and HIV-1 gp120 V3 loop : CCR5 [2] structures which exhibit exceptional agreement with previous experimental findings. The structures shed light into the functional role of the HIV-1 gp120 V3 loop  and CXCR4 / CCR5 residues in the HIV-1 coreceptor activity [1,2]. The HIV-1 gp120 V3 loop : CCR5 structure unravels the blocking mechanism of HIV-1 by maraviroc [2].

We observed that central residue moiety of the specific dual-tropic HIV-1 gp120 V3 loop shares nearly identical structural and energetic properties in complex with both coreceptors [1,2]. We exploited this result, and implemented our well-established de-novodesign protocol [6,7], enriched with MD simulations and free energy calculations, to design a novel 13-residue peptide which would mimic the HIV-1 binding to both coreceptors, and thus, block “universally” the HIV-1 entry [8]. Experiments verified the ability of the newly discovered peptide to (i) recognize both coreceptors, and (ii) “universally” inhibit the HIV-1 entry, in three independent assays of CXCR4-, CCR5- and dual-recognizing viruses [8]. To the best of our knowledge, this is the first peptide which can inhibit the HIV-1 entry to both coreceptors, irrespective of a patient’s mutations [8]. Therefore the novel peptide can provide the basis for a new generation of most needed “universal” anti HIV-1 entry therapeutics [8].


1. Tamamis P, Floudas CA (2013) Molecular recognition of CXCR4 by a dual tropic HIV-1 gp120 V3 loop. Biophys J 105 (6): 1502–1514.

2. Tamamis P, Floudas CA (2014) Molecular recognition of CCR5 by an HIV-1 gp120 V3 loop. PLoS ONE 9 (4): e95767.

3. López de Victoria A, Tamamis P, Kieslich CA, Morikis D (2012) Insights into the Structure, Correlated Motions, and Electrostatic Properties of Two HIV-1 gp120 V3 Loops. PLoS ONE 7 (11): e49925.

4. Tamamis P, Floudas CA (2014) Elucidating a Key Component of Cancer Metastasis: CXCL12 (SDF-1α) Binding to CXCR4. J Chem Inf Model 54 (4): 1174-1188.

5. Tamamis P, Floudas CA (2014) Elucidating a Key Anti-HIV-1 and Cancer-Associated Axis: CCL5 (Rantes) Binding to CCR5. Paper Under Review.

6. Tamamis et al. (2012) Molecular dynamics in drug design: new generations of compstatin analogs. Chem Biol Drug Des 79 (5): 703-718.

7. Gorham et al. (2013) Novel compstatin family peptides inhibit complement activation by drusen-like deposits in human retinal pigmented epithelial cell cultures. Experimental Eye Research 116: 96-108.

8. Tamamis P, Smadbeck J, Floudas CA (2014) De-novo Design of a Dual Targeted CXCR4/CCR5 Anti HIV-1 Peptide. Paper in preparation. 

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