Optimization of a CXCR4 receptor mimetic peptide — ASN Events
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  3. Optimization of a CXCR4 receptor mimetic peptide

Optimization of a CXCR4 receptor mimetic peptide (#141)

Karen Marlyse Fiebig 1 , Johannes Lach 1 , Barbara Schmidt 2 , Jutta Eichler 1
  1. Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Bavaria, Germany
  2. Universität Regensburg, Regensburg, Bavaria, Germany

The chemokine receptor CXCR4 and its endogenous ligand, the stromal derived factor 1α (SDF-1α), are involved in many physiological processes, as well as diseases like cancer and human immunodeficiency virus 1 (HIV-1) infection. [1] In HIV-1 infection CXCR4 functions as a coreceptor enabling virus entry into its host cell. Interaction of the viral envelope glycoprotein gp120 with CXCR4 triggers conformational changes within gp120 that finally result in the fusion of viral and human cell membranes. [2] Especially the extracellular loops (ECLs) of CXCR4 are involved in binding to gp120. [3]

 

We have previously developed a peptide, termed CX4M1, which represents the three ECLs of CXCR4. This peptide was shown to selectively bind to gp120 of HIV-1 strains that use CXCR4 as a coreceptor for cell entry (X4-tropic), but not to gp120 from CCR5 using HIV-1 [4]. This selectivity was also observed for the interaction of CX4M1 with V3-loop peptides, which present an important part of the coreceptor binding site of gp120 [5]. Furthermore, CX4M1 was shown to selectively inhibit the infection of cells with X4-tropic HIV-1 [4], bind to the endogenous CXCR4 ligand SDF-1α, as well as inhibit SDF-1α signaling [6].

 

Strategies to optimize CX4M1, including extensive sequence modification with special emphasis on charge-exchange variants, sequence truncation, as well as homodimerization, resulted in peptides with considerably improved affinity to gp120 and SDF-1a, respectively, as well as HIV-1 neutralizing capacity.

  1. [1] M. Z. Ratajczak et al., Leukemia 2006, 20, 1915-1924.
  2. [2] E. A. Berger et al., Annu. Rev. Immunol. 1999, 17, 657-700.
  3. [3] T. Dragic, J.Gen. Virol. 2001, 82, 1807-1814.
  4. [4] K. Möbius et al., Chem. Eur. J. 2012, 18, 8292-8295.
  5. [5] A. Groß et al., Front. Immunol. 2013, 4, 257.
  6. [6] A. Groß et al., Bioorg. Med. Chem. 2015, 23, 4050–4055.