Mechanism-based pharmacokinetic (MBPK) models describe the complex plasma kinetics of three antiretrovirals delivered by a long-acting anti-HIV drug combination nanoparticle formulation

Despite the world’s combined efforts, human immunodeficiency virus (HIV), the causative agent of AIDS, remains one of the world’s most serious public health challenges. High genetic variability of HIV complicates the development of anti-HIV vaccine, and there is an actual clinical need for increasing the efficiency of anti-HIV drugs in terms of targeted delivery and controlled release. Tenofovir (TFV), a nucleotide-analog reverse transcriptase inhibitor, has gained wide acceptance as a drug for pre-exposure prophylaxis or treatment of HIV infection. In our study, we explored the potential of tenofovir disoproxil (TFD) adducts with block copolymers of poly(ethylene glycol) monomethyl ether and poly(ethylene phosphoric acid) (mPEG-b-PEPA) as candidates for developing a long-acting/controlled-release formulation of TFV. Two types of mPEG-b-PEPA with numbers of ethylene phosphoric acid (EPA) fragments of 13 and 49 were synthesized by catalytic ring-opening polymerization, and used for preparing four types of adducts with TFD. Antiviral activity of [mPEG-b-PEPA]TFD or tenofovir disoproxil fumarate (TDF) was evaluated using the model of experimental HIV infection in vitro (MT-4/HIV-1IIIB). Judging by the values of the selectivity index (SI), TFD exhibited an up to 14-fold higher anti-HIV activity in the form of mPEG-b-PEPA adducts, thus demonstrating significant promise for further development of long-acting/controlled-release injectable TFV formulations.

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Influence of Vitamin B6 Nutritional Status upon Plasma Kinetics of PLP after I.V. Dosing to Rats

Biochemistry of Vitamin B6 ◽

10.1007/978-3-0348-9308-4_73 ◽

1987 ◽

pp. 407-410

Author(s):

W. Bode ◽

P. Hekman ◽

H. v.d. Berg

Keyword(s):

Nutritional Status ◽

Vitamin B6 ◽

Plasma Kinetics ◽

Kinetics Of

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A Novel gp41-Binding Adnectin with Potent Anti-HIV Activity Is Highly Synergistic when Linked to a CD4-Binding Adnectin

Journal of Virology ◽

10.1128/jvi.00421-18 ◽

2018 ◽

Vol 92 (14) ◽

Cited By ~ 6

Author(s):

David Wensel ◽

Yongnian Sun ◽

Jonathan Davis ◽

Zhufang Li ◽

Sharon Zhang ◽

...

Keyword(s):

Envelope Proteins ◽

Coding Region ◽

Intrinsic Resistance ◽

Target Region ◽

Medical Needs ◽

Spectrum Activity ◽

Conserved Region ◽

Long Acting ◽

Kinetics Of ◽

Hiv 1

ABSTRACTThe N17 region of gp41 in HIV-1 is the most conserved region in gp160. mRNA selection technologies were used to identify an adnectin that binds to this region and inhibits gp41-induced membrane fusion. Additional selection conditions were used to optimize the adnectin to greater potency (5.4 ± 2.6 nM) against HIV-1 and improved binding affinity for an N17-containing helical trimer (0.8 ± 0.4 nM). Resistance to this adnectin mapped to a single Glu-to-Arg change within the N17 coding region. The optimized adnectin (6200_A08) exhibited high potency and broad-spectrum activity against 123 envelope proteins and multiple clinical virus isolates, although certain envelope proteins did exhibit reduced susceptibility to 6200_A08 alone. The reduced potency could not be correlated with sequence changes in the target region and was thought to be the result of faster kinetics of fusion mediated by these envelope proteins. Optimized linkage of 6200_A08 with a previously characterized adnectin targeting CD4 produced a highly synergistic molecule, with the potency of the tandem molecule measured at 37 ± 1 pM. In addition, these tandem molecules now exhibited few potency differences against the same panel of envelope proteins with reduced susceptibility to 6200_A08 alone, providing evidence that they did not have intrinsic resistance to 6200_A08 and that coupling 6200_A08 with the anti-CD4 adnectin may provide a higher effective on rate for gp41 target engagement.IMPORTANCEThere continue to be significant unmet medical needs for patients with HIV-1 infection. One way to improve adherence and decrease the likelihood of drug-drug interactions in HIV-1-infected patients is through the development of long-acting biologic inhibitors. This study describes the development and properties of an adnectin molecule that targets the most conserved region of the gp41 protein and inhibits HIV-1 with good potency. Moreover, when fused to a similar adnectin targeted to the human CD4 protein, the receptor for HIV-1, significant synergies in potency and efficacy are observed. These inhibitors are part of an effort to develop a larger biologic molecule that functions as a long-acting self-administered regimen for patients with HIV-1 infection.

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