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 Editorial

Development of CXCR4 antagonist for treatment of AIDS

Wan-Gang Gu1* and Xuan Zhang2

1Department of Immunology, Zunyi Medical University, Zunyi, Guizhou, 563000, China

2School of Pharmaceutical Science & Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University,
    Kunming Yunnan 650500, China

*Corresponding author : Dr. Wan-Gang Gu, Department of Immunology, Zunyi Medical University, Zunyi, Guizhou, 563000, China,E-mail: wanganggu@outlook.com<;/a>

Submitted: 07-10-2014  Accepted: 07-11-2014  Published:  07-15-2014  

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Article

The C-X-C chemokine receptor 4 (CXCR4) is a seven transmembrane G protein coupled receptor (GPCR) of stromal cell-derived factor-1 (SDF-1). CXCR4 is expressed widely in immune system and central nervous system. The CXCR4/SDF-1 axis plays important role in multiple physiological processes. The binding of SDF-1 to CXCR4 activates multiple downstream pathways. CXCR4 is discovered to play major roles in stem cell migration and hematopoiesis [1, 2]. As early as in the 1990’s, CXCR4 was identified as the co-receptor for infection of HIV into CD4 T lymphocytes [3]. The HIV virus uses CXCR4 as co-receptor was subsequently designated X4-tropic HIV strain. The natural ligand SDF-1 showed antiviral activity by binding to CXCR4 competitively. Although the binding modes of SDF-1 and viral gp120 to CXCR4 are not disclosed to be identical, SDF-1 does show competitive binding with the virus [4]. This indicates that SDF-1/CXCR4 is a potential target for anti-HIV research. Attribute to the important physiological functions, the knockout of SDF-1 or CXCR4 leads to serious even lethal confusion of the physiology system [5, 6]. A feasible strategy to target CXCR4 for anti-HIV research is development of CXCR4 antagonist since non-functional SDF-1 analogues show antiviral activity.

Numerous studies have been performed to develop successful CXCR4 antagonists which can block the HIV infection through CXCR4. Many drug candidates have been reported to interfere HIV infection by functioning as CXCR4 antagonists [7-9]. Generally, those CXCR4 antagonists can be divided into two catalogues: peptide CXCR4 antagonist and non-peptide CXCR4 antagonist. The cyclic CVX15 peptide, the T140 peptide, the FC131peptide and the FC122 peptide are examples of peptide CXCR4 antagonist with anti-HIV activity [10]. The cyclic CVX15 peptide is the modified product from the linear CVX15 peptide. The T140 peptide is derived from polyphemusin II and serves as a scaffold for CXCR4 antagonist design. Based on the identification of the pharmacophore associated with T140, the peptide FC131 was discovered to be a low nanomolar antagonist of CXCR4. Modification of the FC131 leads to the discovery of the FC122 peptide, a more potent CXCR4 antagonist [10]. To stop the virus infection, besides CXCR4, gp160 (gp120 and gp41) and SDF-1 are also effective targets for drug design. The interaction between co-receptor CXCR4 and HIV is mainly an interaction between CXCR4 and viral gp160, especially the V3 region in gp120. The interaction between CXCR4 and the viral gp160 is a complex process. The binding of gp120 is the initiation of virus infection, inducing conformational change of gp41 for co-receptor binding. Gp120 failed to induce CXCR4-G protein interactions in T cells but showed antagonist effect to SDF-1α. The binding affinity of gp120 to CXCR4 was ten times lower than to CD4. So CD4 may plays a role in facilitating the binding to gp120 to CXCR4 [11]. Mimicking the viral gp160 results in peptides with anti-HIV activity. F peptide was synthesized corresponding to the residues 414-434 of gp120 of Bru strain of HIV [12]. 


AMD3100, a bicyclam derivative, is the first promising non-peptide CXCR4 antagonist [7]. Based on the potent anti-HIV activity, AMD3100 had been approved for clinical trial in patients infected with HIV. But AMD3100 was terminated for treatment of HIV infection for the cardiac related side effect [13, 14]. Although AMD3100 was finally proved not suitable for treatment of AIDS, it has been widely applied in stem cell and cancer related research [15, 16]. Following AMD3100, other small molecule CXCR4 antagonists such as ADM070 and AMD3465 have been developed for anti-HIV research [8, 17]. The AMD compounds are representative of non-peptide CXCR4 antagonists. The C-C chemokine receptor 5 (CCR5) is the co-receptor for infection of HIV into macrophage [18]. Similar with CXCR4, CCR5 is also regarded as an important target to inhibit HIV infection. Different from the target of CXCR4, the first CCR5 antagonist, maraviroc, has been approved by FDA for clinical application [19]. The approval of CCR5 antagonist encourages efforts in CXCR4 antagonist development. The development of a successful CXCR4 antagonist is not a plain sailing. It is a long term process and multiple positive factors are involved in this course. Among all the factors, the target itself is the most important one. Five CXCR4 crystal structures together with small molecule antagonist IT1t and cyclic CVX15 peptide were disclosed in 2010 [20]. With further understanding of the CXCR4 structure, more precise and useful information is provided. This may greatly accelerate the design of novel CXCR4 antagonist.



Driving retirement has been shown to have a negative impact upon older drivers, carers, family members and doctor-patient relationship [6]. Empowering older drivers with dementia to plan for driving retirement aligns with the ethical principles of autonomy, beneficence and non-maleficence [6]. The arrangement of alternative forms of transport is crucial when considering retirement from driving. A pre-planned strategy which addresses the transition to non-driving obviates the need for clinicians to insist upon abrupt licence withdrawal when a patient becomes clearly unsafe. Adopting a sensitive approach to a potentially difficult physician-patient encounter is of paramount importance. The advent of a decision aid tailored for drivers with dementia has the potential to serve as a helpful resource [7]. Individuals who read this brief booklet experience reduced decisional conflict and exhibit higher knowledge scores [8]. It would appear that non-threatening engagement trumps more paternalistic, and perhaps alienating, methods.


Considering the important physiological role, CXCR4 is not suitable for deletion from the human genome. Although CXCR4 modification based gene therapy may be another choice, CXCR4 based gene therapy is far from clinical application. The major consideration is the long term safety. As mentioned above, CXCR4 is involved in many important physiological activities, it is very difficult to thoroughly evaluate the consequences of gene therapy. Therefore, development of CXCR4 antagonist is a more feasible strategy for this target.

 Acknowledgements

This work was partially supported by the United Foundation of Guizhou (Qiankehe J LKZ[2013]21) and the seed grant from Zunyi Medical University for newly recruited talents to Dr. Wan-Gang Gu.

References

 References

1. Juarez J, Bendall L. SDF-1 and CXCR4 in normal and malignant hematopoiesis. Histol Histopathol .2004, 19(1): 299-309.

2. Hirbe AC, Rubin J, Uluçkan O, Morgan EA, Eagleton MC, et al. Disruption of CXCR4 enhances osteoclastogenesis and tumor growth in bone. Proc Natl Acad Sci U S A .2007, 104(35): 14062-14067.

3.Endres MJ, Clapham PR,  Marsh M, Ahuja M, Turner JD, et al.  CD4-independent infection by HIV-2 is mediated by fusin/CXCR4. Cell .1996, 87(4): 745-756.

4. Oberlin E, Amara A, Bachelerie F, Bessia C, Virelizier JL,  et al. The CXC chemokine SDF-1 is the ligand for LESTR/fusin and prevents infection by T-cell-line-adapted HIV-1. Nature.1996, 382 (6594): 833-835.

5. Hassan S, Ferrario C, Saragovi U, Quenneville L, Gaboury L, et al. The influence of tumor-host interactions in the stromal cell-derived factor-1/CXCR4 ligand/receptor axis in determining metastatic risk in breast cancer.  Am J Pathol.2009, 175(1): 66-73.

6. Sierra-Aragon S, Walter H. Targets for inhibition of HIV replication: entry, enzyme action, release and maturation. Intervirology. 2012, 55(2): 84-97.

7. Donzella GA, Schols D, Lin SW, Este JA, Nagashima KA, et al. AMD3100, a small molecule inhibitor of HIV-1 entry via the CXCR4 co-receptor. Nat Med.1998, 4(1); 72-77.

8. Nyunt MM, Becker S, MacFarland RT, Chee P, Scarborough R, et al. Pharmacokinetic effect of AMD070, an Oral CXCR4 antagonist, on CYP3A4 and CYP2D6 substrates midazolam and dextromethorphan in healthy volunteers. J Acquir Immune Defic Syndr.2008, 47(5): 559-565.

9. Chevigne A, Fischer A, Mathu J, Counson M, Beaupain N,  et al. Selection of a CXCR4 antagonist from a human heavy chain CDR3-derived phage library. FEBS J. 2011, 278(16): 2867-2878.

10.von Recum HA, Pokorski JK. Peptide and protein-based inhibitors of HIV-1 co-receptors. Exp Biol Med (Maywood).2013,238(5):442-449.

11. Staudinger R, Wang X, Bandres JC, et al. HIV-1 envelope is a neutral antagonist to CXCR4 in T-cells. Biochem Biophys Res Commun.2011, 280(4): 1003-1007.

 12. Deng X, Ueda H, Su SB, Gong W, Dunlop NM, et al. A synthetic peptide derived from human immunodeficiency virus type 1 gp120 downregulates the expression and function of chemokine receptors CCR5 and CXCR4 in monocytes by activating the 7-transmembrane G-protein-coupled receptor FPRL1/LXA4R. Blood.1999, 94(4):1165-1173

 13. Dai S, Yuan F, Mu J, Li C, Chen N, et al. Chronic AMD3100 antagonism of SDF-1alpha-CXCR4 exacerbates cardiac dysfunction and remodeling after myocardial infarction. J Mol Cell Cardiol. 2010, 49(4): 587-597.

 14. Jujo K, Ii M, Sekiguchi H, Klyachko E, Misener S, et al.  CXC-chemokine receptor 4 antagonist AMD3100 promotes cardiac functional recovery after ischemia/reperfusion injury via endothelial nitric oxide synthase-dependent mechanism. Circulation. 2013, 127(1): 63-73.

 15. De Clercq, E.  Potential clinical applications of the CXCR4 antagonist bicyclam AMD3100. Mini Rev Med Chem. 2005,5(9): 805-824.

 16. Grignani G, Perissinotto E, Cavalloni G, Carnevale Schianca F, Aglietta M, et al. Clinical use of AMD3100 to mobilize CD34+ cells in patients affected by non-Hodgkin's lymphoma or multiple myeloma. J Clin Oncol. 2005,23(16) 3871-3872: author reply 3872-3873.

 17. Hatse S, Princen K, De Clercq E, Rosenkilde MM, Schwartz TW, et al. AMD3465, a monomacrocyclic CXCR4 antagonist and potent HIV entry inhibitor. Biochem Pharmacol.2005,70(5): 752-761.

 18. Choe H, Farzan M, Sun Y, Sullivan N, Rollins B, et al. The beta-chemokine receptors CCR3 and CCR5 facilitate infection by primary HIV-1 isolates. Cell. 1996, 85(7): 1135-1148.

 19. Lieberman-Blum SS, Fung HB, Bandres JC.  Maraviroc: a CCR5-receptor antagonist for the treatment of HIV-1 infection. Clin Ther.2008,30(7): 1228-1250.

 20.Wu B, Chien EY, Mol CD, Fenalti G, Liu W, et al. Structures of the CXCR4 chemokine GPCR with small-molecule and cyclic peptide antagonists. Science.2010, 330(6007): 1066-1071.

 

Cite this article: Gang G. Development of CXCR4 Antagonist for Treatment of AIDS. J J Aller Immuno. 2014, 1(2): 009.

 

 

 

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