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

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

doi:10.1080/15257770.2014.945649

Cited by 5 publications

(3 citation statements)

References 23 publications

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“…Peptide mimics of other RT binding viral proteins, such as a Vpr protein-derived peptide, also hold promise as peptide inhibitors [183] . Other peptide inhibitors for RT include peptides derived from ribonuclease [184] , [185] , polyarginine transporter molecules [186] , N-methylated peptides that bind RNA [187] , protein targeting RTC [188] , and anti-fungal peptides [189] . Similarly to protease and integrase peptide inhibitors, RT peptide inhibitors also face the problem of low potency (high IC50 values) and thus have not advanced to in vivo evaluation or clinical studies.…”

Section: Targets Of Peptide Inhibitors [154] mentioning

confidence: 99%

Development of peptide inhibitors of HIV transmission

Shi

Nguyen

Cabral

et al. 2016

Bioactive Materials

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Treatment of HIV has long faced the challenge of high mutation rates leading to rapid development of resistance, with ongoing need to develop new methods to effectively fight the infection. Traditionally, early HIV medications were designed to inhibit RNA replication and protein production through small molecular drugs. Peptide based therapeutics are a versatile, promising field in HIV therapy, which continues to develop as we expand our understanding of key protein-protein interactions that occur in HIV replication and infection. This review begins with an introduction to HIV, followed by the biological basis of disease, current clinical management of the disease, therapeutics on the market, and finally potential avenues for improved drug development.

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Section: Targets Of Peptide Inhibitors [154] mentioning

confidence: 99%

Development of peptide inhibitors of HIV transmission

Shi

Nguyen

Cabral

et al. 2016

Bioactive Materials

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“…Recently, several types of nanoassemblies were reported, e.g., squalenoylated (sc) dideoxycytidine (ddC) and didanosine (ddI), forming 100–300 nm micellar assemblies with cholesteryl-PEG or sc-PEG, or poly- l -arginine-fatty acid derivatives of NRTIs that are capable of forming NPs with enhanced cell penetration. , These nanoassemblies demonstrated a 2- to 3-fold decrease of the 50% effective doses (EC 50 ), and anti-HIV activity at EC 50 was as low as 3 μM. We obtained a similar or higher anti-HIV activity (EC 90 ) using single nanodrugs and even better results for dual and triple nanodrug cocktails that imitate therapeutic Combivir and Trizivir cocktails.…”

Section: Discussionmentioning

confidence: 99%

Nanogel-Conjugated Reverse Transcriptase Inhibitors and Their Combinations as Novel Antiviral Agents with Increased Efficacy against HIV-1 Infection

et al. 2015

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Nucleoside Reverse Transcriptase Inhibitors (NRTIs) are an integral part of the current anti-retroviral therapy (ART), which dramatically reduced the mortality from AIDS and turned the disease from lethal to chronic. The further steps in curing the HIV-1 infection must include more effective targeting of infected cells and virus sanctuaries inside the body and modification of drugs and treatment schedules to reduce common complications of the long-term treatment and increase patient compliancy. Here, we describe novel NRTI prodrugs synthesized from cholesteryl-ε-polylysine (CEPL) nanogels by conjugation with NRTI 5′-succinate derivatives (sNRTI). Biodegradability, small particle size and high NRTI loading (30% by weight) of these conjugates; extended drug release, which would allow a weekly administration schedule; high therapeutic index (>1000) with a lower toxicity compared to NRTIs; and efficient accumulation in macrophages known as carriers for HIV-1 infection are among the most attractive properties of new nanodrugs. Nanogel conjugates of Zidovudine (AZT), Lamivudine (3TC) and Abacavir (ABC) have been investigated individually and in formulations similar to clinical NRTI cocktails. Nanodrug formulations demonstrated 10-fold suppression of reverse transcriptase activity (EC90) in HIV-infected macrophages at 2–10, 2–4 and 1–2 μM drug levels, respectively for single nanodrugs, dual and triple nanodrug cocktails. Nanogel conjugate of Lamivudine was the most effective single nanodrug (EC90 2 μM). Nanodrugs showed a more favorable pharmacokinetics compared to free NRTIs. Spared i.v. injections of PEGylated CEPL-sAZT alone could efficiently suppress HIV-1 RT activity to background level in humanized mouse (hu-PBL) HIV model.

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“…This platform was recently used for TAF and demonstrated maintaining drug stability and a controlled, sustained drug release from an SC hydrogel reservoir (through hydrolysis or enzyme-mediated cleavage at the linker site) for 2 months in mice [ 76 ]. Conjugation of ARVs with polypeptides and polysaccharides has previously been shown to improve drug activity and cellular uptake [ 77 – 79 ]. The drugamer technology offers several key advantages, including high drug loading capability, control over drug release rates and degradation kinetics for the depot, and increased drug substance stability due to the molecular architecture of the polymer formulation [ 76 ].…”

Section: Approaches To Improving Existing Arvs For La Hiv Preventionmentioning

confidence: 99%

Long-acting HIV pre-exposure prophylaxis (PrEP) approaches: recent advances, emerging technologies, and development challenges

Agrahari

Anderson

Peet

et al. 2022

Expert Opinion on Drug Delivery

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Introduction: Poor or inconsistent adherence to daily oral pre-exposure prophylaxis (PrEP) has emerged as a key barrier to effective HIV prevention. The advent of potent long-acting (LA) antiretrovirals (ARVs) in conjunction with advances in controlled release technologies has enabled LA ARV drug delivery systems (DDS) capable of providing extended dosing intervals and overcome the challenge of suboptimal drug adherence with daily oral dosing. Areas covered: This review discusses the current state of the LA PrEP field, recent advances, and emerging technologies, including ARV prodrug modifications and new DDS. Technological challenges, knowledge gaps, preclinical testing considerations, and future directions important in the context of clinical translation and implementation of LA HIV PrEP are discussed. Expert opinion: The HIV prevention field is evolving faster than ever and the bar for developing next-generation LA HIV prevention options continues to rise. The requirements for viable LA PrEP products to be implemented in resource-limited settings are challenging, necessitating proactive consideration and product modifications during the design and testing of promising new candidates. If successfully translated, next-generation LA PrEP that are safe, affordable, highly effective, and accepted by both end-users and key stakeholders will offer significant potential to curb the HIV pandemic.

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

Cited by 5 publications

References 23 publications

Development of peptide inhibitors of HIV transmission

Development of peptide inhibitors of HIV transmission

Nanogel-Conjugated Reverse Transcriptase Inhibitors and Their Combinations as Novel Antiviral Agents with Increased Efficacy against HIV-1 Infection

Long-acting HIV pre-exposure prophylaxis (PrEP) approaches: recent advances, emerging technologies, and development challenges

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