Different Stereochemical Requirements for CXCR4 Binding and Signaling Functions As Revealed by an Anti-HIV, <scp>d</scp>-Amino Acid-Containing SMM-Chemokine Ligand

Dong, C.; Kumar, Swagat; Choi, Won‐Tak; Madani, Navid; Tian, Shaomin; An, Jing; Sodroski, Joseph; Huang, Ziwei

doi:10.1021/jm050829u

Cited by 15 publications

(25 citation statements)

References 18 publications

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“…N-(9-fluorenyl)methoxycarbonyl chemistry was employed for the synthesis (23,24). 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) and 1-hydroxybenzotriazole (HOBt) were used as coupling reagents in the presence of diisopropylethylamine (DIEA).…”

Section: Methodsmentioning

confidence: 99%

“…We previously demonstrated how this SMM-chemokine approach could be applied to convert the nonselective vMIP-II into highly selective ligands of CXCR4 or CCR5 in terms of their binding, signaling, and/or antiviral activity (23). We also used a similar strategy to modify the biological and pharmacological properties of SDF-1␣ (24). This is of particular importance because SDF-1␣, the only known naturally occurring ligand for CXCR4, is neurotoxic in the presence or absence of HIV/gp120 (19).…”

Section: Hadmentioning

confidence: 99%

“…RCP189 was also shown to maintain its selectivity toward CCR5, although its binding affinity was weaker than that of RCP188. In another study, we replaced the N-terminal (1-8) sequence module of SDF-1␣, the only natural ligand for CXCR4, with all D-forms of (1-10) residues of vMIP-II (24). Subsequent binding and antiviral assays showed that D-(1-10)-vMIP-II-(9 -68)-SDF-1␣ (RCP222) was not only a selective CXCR4 ligand but also an effective HIV-1 inhibitor.…”

Section: Treatment With Gp120 Smm-chemokines and Various Inhibitorsmentioning

confidence: 99%

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Neuronal Apoptotic Signaling Pathways Probed and Intervened by Synthetically and Modularly Modified (SMM) Chemokines

Choi¹,

Kaul

Kumar³

et al. 2007

Journal of Biological Chemistry

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As the main coreceptors for human immunodeficiency virus type 1 (HIV-1) entry, CXCR4 and CCR5 play important roles in HIV-associated dementia (HAD). HIV-1 glycoprotein gp120 contributes to HAD by causing neuronal damage and death, either directly by triggering apoptotic pathways or indirectly by stimulating glial cells to release neurotoxins. Here, to understand the mechanism of CXCR4 or CCR5 signaling in neuronal apoptosis associated with HAD, we have applied synthetically and modularly modified (SMM)-chemokine analogs derived from natural stromal cell-derived factor-1␣ or viral macrophage inflammatory protein-II as chemical probes of the mechanism(s) whereby these SMM-chemokines prevent or promote neuronal apoptosis. We show that inherently neurotoxic natural ligands of CXCR4, such as stromal cell-derived factor-1␣ or viral macrophage inflammatory protein-II, can be modified to protect neurons from apoptosis induced by CXCR4-preferring gp120 IIIB , and that the inhibition of CCR5 by antagonist SMM-chemokines, unlike neuroprotective CCR5 natural ligands, leads to neurotoxicity by activating a p38 mitogen-activated protein kinase (MAPK)-dependent pathway. Furthermore, we discover distinct signaling pathways activated by different chemokine ligands that are either natural agonists or synthetic antagonists, thus demonstrating a chemical biology strategy of using chemically engineered inhibitors of chemokine receptors to study the signaling mechanism of neuronal apoptosis and survival.

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Section: Methodsmentioning

confidence: 99%

Section: Hadmentioning

confidence: 99%

Section: Treatment With Gp120 Smm-chemokines and Various Inhibitorsmentioning

confidence: 99%

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Neuronal Apoptotic Signaling Pathways Probed and Intervened by Synthetically and Modularly Modified (SMM) Chemokines

Choi¹,

Kaul

Kumar³

et al. 2007

Journal of Biological Chemistry

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“…The automated stepwise incorporation of protected amino acids was performed using an Applied Biosystems 433A peptide synthesizer (Foster City, CA) with a CLEAR amide resin (Peptides International, Louisville, KY) as the solid support, as described previously (9, 13, 23). 9-Fluorenylmethoxy carbonyl chemistry was employed for the synthesis (13,23). 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate and N-hydroxybenzotriazole were used as coupling reagents in the presence of diisopropylethylamine.…”

Section: Methodsmentioning

confidence: 99%

“…To address this issue of selectivity in chemokine ligandreceptor interactions, we have developed a chemical and protein structure-based strategy that employs synthetically and modularly modified (SMM) chemokines (8,9,13,23). In this approach, synthetic chemistry is applied to introduce unnatural amino acids or novel chemical modifications into the important functional-sequence modules of native chemokines, such as vMIP-II and SDF-1␣, to yield new molecules with high receptor selectivity and other improved biological and pharmacological properties.…”

mentioning

confidence: 99%

Crystal Structure and Structural Mechanism of a Novel Anti-Human Immunodeficiency Virus andd-Amino Acid-Containing Chemokine

Liu¹,

Madani

Liu

et al. 2007

J Virol

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Chemokines and their receptors play important roles in normal physiological functions and the pathogeneses of a wide range of human diseases, including the entry of human immunodeficiency virus type 1 (HIV-1). However, the use of natural chemokines to probe receptor biology or to develop therapeutic drugs is limited by their lack of selectivity and the poor understanding of mechanisms in ligand-receptor recognition. We addressed these issues by combining chemical and structural biology in research into molecular recognition and inhibitor design. Specifically, the concepts of chemical biology were used to develop synthetically and modularly modified (SMM) chemokines that are unnatural and yet have properties improved over those of natural chemokines in terms of receptor selectivity, affinity, and the ability to explore receptor functions. This was followed by using structural biology to determine the structural basis for synthetically perturbed ligand-receptor selectivity. As a proof-of-principle for this combined chemical and structural-biology approach, we report a novel D-amino acid-containing SMM-chemokine designed based on the natural chemokine called viral macrophage inflammatory protein II (vMIP-II). The incorporation of unnatural D-amino acids enhanced the affinity of this molecule for CXCR4 but significantly diminished that for CCR5 or CCR2, thus yielding much more selective recognition of CXCR4 than wild-type vMIP-II. This D-amino acid-containing chemokine also showed more potent and specific inhibitory activity against HIV-1 entry via CXCR4 than natural chemokines. Furthermore, the high-resolution crystal structure of this D-amino acid-containing chemokine and a molecular-modeling study of its complex with CXCR4 provided the structure-based mechanism for the selective interaction between the ligand and chemokine receptors and the potent anti-HIV activity of D-amino acid-containing chemokines.Protein-protein interactions play important roles in a wide variety of physiological and pathological processes. The inhibition or promotion of these interactions, by either small or relatively large synthetic molecules, is of great interest for understanding the mechanism of biological recognition and developing novel therapeutic agents. In this regard, much progress has been made in recent years (3,8,29). This type of chemical research in protein-protein interactions is becoming increasingly important, especially in the postgenomic era, as chemically synthesized regulators of protein-protein interactions can be used to study the functions of new proteins uncovered by genomic-research efforts.One of the most important and challenging questions in the field of protein-protein interactions and development of intervening agents is selectivity in protein-protein interactions. Specifically, what are the mechanisms that dictate how one protein recognizes another out of a myriad of biological molecules, especially when the interacting partners in the same protein family share structural or functional homology? Alternativ...

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Engineering and screening the N-terminus of chemokines for drug discovery

Chevigné

Fiévez

Schmit

et al. 2011

Biochemical Pharmacology

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Different Stereochemical Requirements for CXCR4 Binding and Signaling Functions As Revealed by an Anti-HIV, d-Amino Acid-Containing SMM-Chemokine Ligand

Cited by 15 publications

References 18 publications

Neuronal Apoptotic Signaling Pathways Probed and Intervened by Synthetically and Modularly Modified (SMM) Chemokines

Neuronal Apoptotic Signaling Pathways Probed and Intervened by Synthetically and Modularly Modified (SMM) Chemokines

Crystal Structure and Structural Mechanism of a Novel Anti-Human Immunodeficiency Virus andd-Amino Acid-Containing Chemokine

Engineering and screening the N-terminus of chemokines for drug discovery

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