Design, Synthesis, Antiviral Activity, and Pre-Formulation Development of Poly- L -Arginine-Fatty Acyl Derivatives of Nucleoside Reverse Transcriptase Inhibitors

Bhanu P. Pemmaraju; Swapnil Malekar; Hitesh K. Agarwal; Rakesh K. Tiwari; Donghoon Oh; Gustavo F. Doncel; David R. Worthen; Keykavous Parang

doi:10.1080/15257770.2014.945649

Design, Synthesis, Antiviral Activity, and Pre-Formulation Development of Poly- L -Arginine-Fatty Acyl Derivatives of Nucleoside Reverse Transcriptase Inhibitors

Bhanu P. Pemmaraju, Swapnil Malekar, Hitesh K. Agarwal, Rakesh K. Tiwari, Donghoon Oh, Gustavo F. Doncel, David R. Worthen, Keykavous Parang

Research output: Contribution to journal › Article › peer-review

5 Scopus citations

Abstract

The objective of this work was to design conjugates of anti-HIV nucleosides conjugated with fatty acids and cell-penetrating poly-L-arginine (polyArg) peptides. Three conjugates of polyArg cell-penetrating peptides with fatty acyl derivatives of alovudine (FLT), lamivudine (3TC), and emtricitabine (FTC) were synthesized. In general, the compounds exhibited anti-HIV activity against X4 and R5 cell-free virus with EC₅₀ values of 1.5-16.6 μM. FLT-CO-(CH₂)12-CO-(Arg)₇ exhibited EC₅₀ values of 2.9 μM and 3.1 μM against X4 and R5 cell-free virus, respectively. The FLT conjugate was selected for further preformulation studies by determination of solution state degradation and lipid solubility. The compound was found to be stable in neutral and oxidative conditions and moderately stable in heated conditions.

Original language	English (US)
Pages (from-to)	1-15
Number of pages	15
Journal	Nucleosides, Nucleotides and Nucleic Acids
Volume	34
Issue number	1
DOIs	https://doi.org/10.1080/15257770.2014.945649
State	Published - Jan 2 2015
Externally published	Yes

Keywords

anti-HIV agents
fatty acids
lipophilicity
nucleosides
polyarginine
reverse transcriptase

ASJC Scopus subject areas

Genetics
Biochemistry
Molecular Medicine

Access to Document

10.1080/15257770.2014.945649

Cite this

Pemmaraju, B. P., Malekar, S., Agarwal, H. K., Tiwari, R. K., Oh, D., Doncel, G. F., Worthen, D. R., & Parang, K. (2015). Design, Synthesis, Antiviral Activity, and Pre-Formulation Development of Poly- L -Arginine-Fatty Acyl Derivatives of Nucleoside Reverse Transcriptase Inhibitors. Nucleosides, Nucleotides and Nucleic Acids, 34(1), 1-15. https://doi.org/10.1080/15257770.2014.945649

Design, Synthesis, Antiviral Activity, and Pre-Formulation Development of Poly- L -Arginine-Fatty Acyl Derivatives of Nucleoside Reverse Transcriptase Inhibitors. / Pemmaraju, Bhanu P.; Malekar, Swapnil; Agarwal, Hitesh K. et al.
In: Nucleosides, Nucleotides and Nucleic Acids, Vol. 34, No. 1, 02.01.2015, p. 1-15.

Research output: Contribution to journal › Article › peer-review

Pemmaraju, BP, Malekar, S, Agarwal, HK, Tiwari, RK, Oh, D, Doncel, GF, Worthen, DR & Parang, K 2015, 'Design, Synthesis, Antiviral Activity, and Pre-Formulation Development of Poly- L -Arginine-Fatty Acyl Derivatives of Nucleoside Reverse Transcriptase Inhibitors', Nucleosides, Nucleotides and Nucleic Acids, vol. 34, no. 1, pp. 1-15. https://doi.org/10.1080/15257770.2014.945649

@article{11a4445d844946678bca7c643c668819,

title = "Design, Synthesis, Antiviral Activity, and Pre-Formulation Development of Poly- L -Arginine-Fatty Acyl Derivatives of Nucleoside Reverse Transcriptase Inhibitors",

abstract = "The objective of this work was to design conjugates of anti-HIV nucleosides conjugated with fatty acids and cell-penetrating poly-L-arginine (polyArg) peptides. Three conjugates of polyArg cell-penetrating peptides with fatty acyl derivatives of alovudine (FLT), lamivudine (3TC), and emtricitabine (FTC) were synthesized. In general, the compounds exhibited anti-HIV activity against X4 and R5 cell-free virus with EC50 values of 1.5-16.6 μM. FLT-CO-(CH2)12-CO-(Arg)7 exhibited EC50 values of 2.9 μM and 3.1 μM against X4 and R5 cell-free virus, respectively. The FLT conjugate was selected for further preformulation studies by determination of solution state degradation and lipid solubility. The compound was found to be stable in neutral and oxidative conditions and moderately stable in heated conditions.",

keywords = "anti-HIV agents, fatty acids, lipophilicity, nucleosides, polyarginine, reverse transcriptase",

author = "Pemmaraju, {Bhanu P.} and Swapnil Malekar and Agarwal, {Hitesh K.} and Tiwari, {Rakesh K.} and Donghoon Oh and Doncel, {Gustavo F.} and Worthen, {David R.} and Keykavous Parang",

year = "2015",

month = jan,

day = "2",

doi = "10.1080/15257770.2014.945649",

language = "English (US)",

volume = "34",

pages = "1--15",

journal = "Nucleosides, Nucleotides and Nucleic Acids",

issn = "1525-7770",

publisher = "Taylor and Francis Ltd.",

number = "1",

}

TY - JOUR

T1 - Design, Synthesis, Antiviral Activity, and Pre-Formulation Development of Poly- L -Arginine-Fatty Acyl Derivatives of Nucleoside Reverse Transcriptase Inhibitors

AU - Pemmaraju, Bhanu P.

AU - Malekar, Swapnil

AU - Agarwal, Hitesh K.

AU - Tiwari, Rakesh K.

AU - Oh, Donghoon

AU - Doncel, Gustavo F.

AU - Worthen, David R.

AU - Parang, Keykavous

PY - 2015/1/2

Y1 - 2015/1/2

N2 - The objective of this work was to design conjugates of anti-HIV nucleosides conjugated with fatty acids and cell-penetrating poly-L-arginine (polyArg) peptides. Three conjugates of polyArg cell-penetrating peptides with fatty acyl derivatives of alovudine (FLT), lamivudine (3TC), and emtricitabine (FTC) were synthesized. In general, the compounds exhibited anti-HIV activity against X4 and R5 cell-free virus with EC50 values of 1.5-16.6 μM. FLT-CO-(CH2)12-CO-(Arg)7 exhibited EC50 values of 2.9 μM and 3.1 μM against X4 and R5 cell-free virus, respectively. The FLT conjugate was selected for further preformulation studies by determination of solution state degradation and lipid solubility. The compound was found to be stable in neutral and oxidative conditions and moderately stable in heated conditions.

AB - The objective of this work was to design conjugates of anti-HIV nucleosides conjugated with fatty acids and cell-penetrating poly-L-arginine (polyArg) peptides. Three conjugates of polyArg cell-penetrating peptides with fatty acyl derivatives of alovudine (FLT), lamivudine (3TC), and emtricitabine (FTC) were synthesized. In general, the compounds exhibited anti-HIV activity against X4 and R5 cell-free virus with EC50 values of 1.5-16.6 μM. FLT-CO-(CH2)12-CO-(Arg)7 exhibited EC50 values of 2.9 μM and 3.1 μM against X4 and R5 cell-free virus, respectively. The FLT conjugate was selected for further preformulation studies by determination of solution state degradation and lipid solubility. The compound was found to be stable in neutral and oxidative conditions and moderately stable in heated conditions.

KW - anti-HIV agents

KW - fatty acids

KW - lipophilicity

KW - nucleosides

KW - polyarginine

KW - reverse transcriptase

UR - http://www.scopus.com/inward/record.url?scp=84943519875&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84943519875&partnerID=8YFLogxK

U2 - 10.1080/15257770.2014.945649

DO - 10.1080/15257770.2014.945649

M3 - Article

C2 - 25513860

AN - SCOPUS:84943519875

SN - 1525-7770

VL - 34

SP - 1

EP - 15

JO - Nucleosides, Nucleotides and Nucleic Acids

JF - Nucleosides, Nucleotides and Nucleic Acids

IS - 1

ER -

Design, Synthesis, Antiviral Activity, and Pre-Formulation Development of Poly- L -Arginine-Fatty Acyl Derivatives of Nucleoside Reverse Transcriptase Inhibitors

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this