Design and cellular kinetics of dansyl-labeled CADA derivatives with anti-HIV and CD4 receptor down-modulating activity

Kurt Vermeire, Andrea Lisco, Jean-Charles B. Grivel, Emily Scarbrough, Kaka Dey, Noah Duffy, Leonid Margolis, Thomas W. Bell, Dominique Schols

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

A new class of anti-retrovirals, cyclotriazadisulfonamide (CADA) and its derivatives, specifically down-regulate CD4, the main receptor of HIV, and prevent HIV infection in vitro. In this work, several CADA derivatives, chemically labeled with a fluorescent dansyl group, were evaluated for their biological features and cellular uptake kinetics. We identified a derivative KKD-016 with antiviral and CD4 down-modulating capabilities similar to those of the parental compound CADA. By using flow cytometry, we demonstrated that the dose-dependent cellular uptake of this derivative correlated with CD4 down-modulation. The uptake and activity of the dansyl-labeled compounds were not dependent on the level of expression of CD4 at the cell surface. Removal of the CADA compounds from the cell culture medium resulted in their release from the cells followed by a complete restoration of CD4 expression. The inability of several fluorescent CADA derivatives to down-modulate CD4 was not associated with their lower cellular uptake and was not reversed by facilitating their cell penetration by a surfactant. These results prove the successful integration of the dansyl fluorophore into the chemical structure of a CD4 down-modulating anti-HIV compound, and show the feasibility of tracking a receptor and its down-modulator simultaneously. These fluorescent CADA analogs with reversible CD4 down-regulating potency can now be applied in further studies on receptor modulation, and in the exploration of their potentials as preventive and therapeutic anti-HIV drugs.

Original languageEnglish
Pages (from-to)566-578
Number of pages13
JournalBiochemical Pharmacology
Volume74
Issue number4
DOIs
Publication statusPublished - 15 Aug 2007
Externally publishedYes

Fingerprint

HIV Receptors
CD4 Antigens
Derivatives
Dansyl Compounds
Kinetics
HIV
Anti-HIV Agents
Surface-Active Agents
HIV Infections
Antiviral Agents
Culture Media
Modulation
Flow Cytometry
Down-Regulation
Cell Culture Techniques
Flow cytometry
Fluorophores
Cell culture
Modulators
Restoration

Keywords

  • Anti-HIV
  • CADA
  • CD4 receptor
  • Cellular kinetics
  • Dansyl
  • Reversible Down-modulation

ASJC Scopus subject areas

  • Pharmacology

Cite this

Design and cellular kinetics of dansyl-labeled CADA derivatives with anti-HIV and CD4 receptor down-modulating activity. / Vermeire, Kurt; Lisco, Andrea; Grivel, Jean-Charles B.; Scarbrough, Emily; Dey, Kaka; Duffy, Noah; Margolis, Leonid; Bell, Thomas W.; Schols, Dominique.

In: Biochemical Pharmacology, Vol. 74, No. 4, 15.08.2007, p. 566-578.

Research output: Contribution to journalArticle

Vermeire, Kurt ; Lisco, Andrea ; Grivel, Jean-Charles B. ; Scarbrough, Emily ; Dey, Kaka ; Duffy, Noah ; Margolis, Leonid ; Bell, Thomas W. ; Schols, Dominique. / Design and cellular kinetics of dansyl-labeled CADA derivatives with anti-HIV and CD4 receptor down-modulating activity. In: Biochemical Pharmacology. 2007 ; Vol. 74, No. 4. pp. 566-578.
@article{09f43666e07946ef8afef55a34a30c15,
title = "Design and cellular kinetics of dansyl-labeled CADA derivatives with anti-HIV and CD4 receptor down-modulating activity",
abstract = "A new class of anti-retrovirals, cyclotriazadisulfonamide (CADA) and its derivatives, specifically down-regulate CD4, the main receptor of HIV, and prevent HIV infection in vitro. In this work, several CADA derivatives, chemically labeled with a fluorescent dansyl group, were evaluated for their biological features and cellular uptake kinetics. We identified a derivative KKD-016 with antiviral and CD4 down-modulating capabilities similar to those of the parental compound CADA. By using flow cytometry, we demonstrated that the dose-dependent cellular uptake of this derivative correlated with CD4 down-modulation. The uptake and activity of the dansyl-labeled compounds were not dependent on the level of expression of CD4 at the cell surface. Removal of the CADA compounds from the cell culture medium resulted in their release from the cells followed by a complete restoration of CD4 expression. The inability of several fluorescent CADA derivatives to down-modulate CD4 was not associated with their lower cellular uptake and was not reversed by facilitating their cell penetration by a surfactant. These results prove the successful integration of the dansyl fluorophore into the chemical structure of a CD4 down-modulating anti-HIV compound, and show the feasibility of tracking a receptor and its down-modulator simultaneously. These fluorescent CADA analogs with reversible CD4 down-regulating potency can now be applied in further studies on receptor modulation, and in the exploration of their potentials as preventive and therapeutic anti-HIV drugs.",
keywords = "Anti-HIV, CADA, CD4 receptor, Cellular kinetics, Dansyl, Reversible Down-modulation",
author = "Kurt Vermeire and Andrea Lisco and Grivel, {Jean-Charles B.} and Emily Scarbrough and Kaka Dey and Noah Duffy and Leonid Margolis and Bell, {Thomas W.} and Dominique Schols",
year = "2007",
month = "8",
day = "15",
doi = "10.1016/j.bcp.2007.05.018",
language = "English",
volume = "74",
pages = "566--578",
journal = "Biochemical Pharmacology",
issn = "0006-2952",
publisher = "Elsevier Inc.",
number = "4",

}

TY - JOUR

T1 - Design and cellular kinetics of dansyl-labeled CADA derivatives with anti-HIV and CD4 receptor down-modulating activity

AU - Vermeire, Kurt

AU - Lisco, Andrea

AU - Grivel, Jean-Charles B.

AU - Scarbrough, Emily

AU - Dey, Kaka

AU - Duffy, Noah

AU - Margolis, Leonid

AU - Bell, Thomas W.

AU - Schols, Dominique

PY - 2007/8/15

Y1 - 2007/8/15

N2 - A new class of anti-retrovirals, cyclotriazadisulfonamide (CADA) and its derivatives, specifically down-regulate CD4, the main receptor of HIV, and prevent HIV infection in vitro. In this work, several CADA derivatives, chemically labeled with a fluorescent dansyl group, were evaluated for their biological features and cellular uptake kinetics. We identified a derivative KKD-016 with antiviral and CD4 down-modulating capabilities similar to those of the parental compound CADA. By using flow cytometry, we demonstrated that the dose-dependent cellular uptake of this derivative correlated with CD4 down-modulation. The uptake and activity of the dansyl-labeled compounds were not dependent on the level of expression of CD4 at the cell surface. Removal of the CADA compounds from the cell culture medium resulted in their release from the cells followed by a complete restoration of CD4 expression. The inability of several fluorescent CADA derivatives to down-modulate CD4 was not associated with their lower cellular uptake and was not reversed by facilitating their cell penetration by a surfactant. These results prove the successful integration of the dansyl fluorophore into the chemical structure of a CD4 down-modulating anti-HIV compound, and show the feasibility of tracking a receptor and its down-modulator simultaneously. These fluorescent CADA analogs with reversible CD4 down-regulating potency can now be applied in further studies on receptor modulation, and in the exploration of their potentials as preventive and therapeutic anti-HIV drugs.

AB - A new class of anti-retrovirals, cyclotriazadisulfonamide (CADA) and its derivatives, specifically down-regulate CD4, the main receptor of HIV, and prevent HIV infection in vitro. In this work, several CADA derivatives, chemically labeled with a fluorescent dansyl group, were evaluated for their biological features and cellular uptake kinetics. We identified a derivative KKD-016 with antiviral and CD4 down-modulating capabilities similar to those of the parental compound CADA. By using flow cytometry, we demonstrated that the dose-dependent cellular uptake of this derivative correlated with CD4 down-modulation. The uptake and activity of the dansyl-labeled compounds were not dependent on the level of expression of CD4 at the cell surface. Removal of the CADA compounds from the cell culture medium resulted in their release from the cells followed by a complete restoration of CD4 expression. The inability of several fluorescent CADA derivatives to down-modulate CD4 was not associated with their lower cellular uptake and was not reversed by facilitating their cell penetration by a surfactant. These results prove the successful integration of the dansyl fluorophore into the chemical structure of a CD4 down-modulating anti-HIV compound, and show the feasibility of tracking a receptor and its down-modulator simultaneously. These fluorescent CADA analogs with reversible CD4 down-regulating potency can now be applied in further studies on receptor modulation, and in the exploration of their potentials as preventive and therapeutic anti-HIV drugs.

KW - Anti-HIV

KW - CADA

KW - CD4 receptor

KW - Cellular kinetics

KW - Dansyl

KW - Reversible Down-modulation

UR - http://www.scopus.com/inward/record.url?scp=34447288211&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34447288211&partnerID=8YFLogxK

U2 - 10.1016/j.bcp.2007.05.018

DO - 10.1016/j.bcp.2007.05.018

M3 - Article

VL - 74

SP - 566

EP - 578

JO - Biochemical Pharmacology

JF - Biochemical Pharmacology

SN - 0006-2952

IS - 4

ER -