Recent Patents and Emerging Therapeutics for HIV Infections: a Focus on Protease Inhibitors

Patel, Mitesh; Mandava, Nanda K.; Vadlapatla, Ramya Krishna; Mitra, Ashim K.

doi:10.4155/ppa.13.33

Cited by 5 publications

(4 citation statements)

References 129 publications

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“…As a result of negligible brain LPV absorption, the virus harboring in brain parenchyma remains unchecked resulting in a HIV-1 sanctuary site and AIDS-related dementia. Hence to achieve therapeutic concentrations, large doses of PIs are administered which results in unacceptable systemic side effects [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

Amino Acid Prodrugs: An Approach to Improve the Absorption of HIV-1 Protease Inhibitor, Lopinavir

et al. 2014

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Poor systemic concentrations of lopinavir (LPV) following oral administration occur due to high cellular efflux by P-glycoprotein (P-gp) and multidrug resistance-associated proteins (MRPs) and extensive metabolism by CYP3A4 enzymes. In this study, amino acid prodrugs of LPV were designed and investigated for their potential to circumvent efflux processes and first pass effects. Three amino acid prodrugs were synthesized by conjugating isoleucine, tryptophan and methionine to LPV. Prodrug formation was confirmed by the LCMS/MS and NMR technique. Interaction of LPV prodrugs with efflux proteins were carried out in P-gp (MDCK-MDR1) and MRP2 (MDCK-MRP2) transfected cells. Aqueous solubility studies demonstrated that prodrugs generate higher solubility relative to LPV. Prodrugs displayed higher stability under acidic conditions and degraded significantly with rise in pH. Uptake and transport data suggested that prodrugs carry significantly lower affinity towards P-gp and MRP2 relative to LPV. Moreover, prodrugs exhibited higher liver microsomal stability relative to LPV. Hence, amino acid prodrug modification might be a viable approach for enhancing LPV absorption across intestinal epithelial and brain endothelial cells which expresses high levels of P-gp and MRP2.

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Section: Introductionmentioning

confidence: 99%

Amino Acid Prodrugs: An Approach to Improve the Absorption of HIV-1 Protease Inhibitor, Lopinavir

et al. 2014

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“…These drugs exhibit extensive binding to plasma proteins (90 – 99%), predominantly to two proteins, albumin and α 1 -acid glycoprotein. Long-term side effects include visceral fat accumulation (lipodystrophy or fat redistribution syndrome) and metabolic disorders (insulin resistance, hyperlip-idemia, hypertriglyceridemia) [28]. In order to enhance their pharmacokinetic profile, all PIs (except for nelfinavir) are boosted with low-dose ritonavir.…”

Section: Antiretroviral Therapymentioning

confidence: 99%

Clinically relevant drug–drug interactions between antiretrovirals and antifungals

Vadlapatla

Patel

Paturi

et al. 2014

Expert Opinion on Drug Metabolism & Toxicology

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Introduction Complete delineation of the HIV-1 life cycle has resulted in the development of several antiretroviral drugs. Twenty-five therapeutic agents belonging to five different classes are currently available for the treatment of HIV-1 infections. Advent of triple combination antiretroviral therapy has significantly lowered the mortality rate in HIV patients. However, fungal infections still represent major opportunistic diseases in immunocompromised patients worldwide. Areas covered Antiretroviral drugs that target enzymes and/or proteins indispensable for viral replication are discussed in this article. Fungal infections, causative organisms, epidemiology and preferred treatment modalities are also outlined. Finally, observed/predicted drug-drug interactions between antiretrovirals and antifungals are summarized along with clinical recommendations. Expert opinion Concomitant use of amphotericin B and tenofovir must be closely monitored for renal functioning. Due to relatively weak interactive potential with the CYP450 system, fluconazole is the preferred antifungal drug. High itraconazole doses (> 200 mg/day) are not advised in patients receiving booster protease inhibitor (PI) regimen. Posaconazole is contraindicated in combination with either efavirenz or fosamprenavir. Moreover, voriconazole is contraindicated with high-dose ritonavir-boosted PI. Echino-candins may aid in overcoming the limitations of existing antifungal therapy. An increasing number of documented or predicted drug-drug interactions and therapeutic drug monitoring may aid in the management of HIV-associated opportunistic fungal infections.

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“…S1 in Supporting Information). The enzyme cleaves viral polyproteins at specific sites, contributing to the mature structure and function of HIV-1 proteins 3 , 4 . Blocking the PR active site by PIs is crucial to prevent the mature virion assembly, viral replication, and increased viral load.…”

Section: Introductionmentioning

confidence: 99%

FMO-guided design of darunavir analogs as HIV-1 protease inhibitors

Chuntakaruk,

Hengphasatporn,

Shigeta

et al. 2024

Sci Rep

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The prevalence of HIV-1 infection continues to pose a significant global public health issue, highlighting the need for antiretroviral drugs that target viral proteins to reduce viral replication. One such target is HIV-1 protease (PR), responsible for cleaving viral polyproteins, leading to the maturation of viral proteins. While darunavir (DRV) is a potent HIV-1 PR inhibitor, drug resistance can arise due to mutations in HIV-1 PR. To address this issue, we developed a novel approach using the fragment molecular orbital (FMO) method and structure-based drug design to create DRV analogs. Using combinatorial programming, we generated novel analogs freely accessible via an on-the-cloud mode implemented in Google Colab, Combined Analog generator Tool (CAT). The designed analogs underwent cascade screening through molecular docking with HIV-1 PR wild-type and major mutations at the active site. Molecular dynamics (MD) simulations confirmed the assess ligand binding and susceptibility of screened designed analogs. Our findings indicate that the three designed analogs guided by FMO, 19–0–14–3, 19–8–10–0, and 19–8–14–3, are superior to DRV and have the potential to serve as efficient PR inhibitors. These findings demonstrate the effectiveness of our approach and its potential to be used in further studies for developing new antiretroviral drugs.

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Recent Patents and Emerging Therapeutics for HIV Infections: a Focus on Protease Inhibitors

Cited by 5 publications

References 129 publications

Amino Acid Prodrugs: An Approach to Improve the Absorption of HIV-1 Protease Inhibitor, Lopinavir

Amino Acid Prodrugs: An Approach to Improve the Absorption of HIV-1 Protease Inhibitor, Lopinavir

Clinically relevant drug–drug interactions between antiretrovirals and antifungals

FMO-guided design of darunavir analogs as HIV-1 protease inhibitors

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