Covalently Targeted Highly Conserved Tyr318 to Improve the Drug Resistance Profiles of HIV-1 NNRTIs: A Proof-of-Concept Study

Zhou, Zhenzhen; Meng, Bairu; An, Jiaqi; Zhao, Fabao; Sun, Yun; Zhang, Dan; Wang, Wenna; Gao, Shenghua; Lei, Yu; Dun, Caiyun; Clercq, Erik De; Pannecouque, Christophe; Zhan, Peng; Kang, Dongwei; Liu, Xinyong

doi:10.3390/ijms24021215

Cited by 4 publications

(2 citation statements)

References 23 publications

(27 reference statements)

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“…In Scheme 3, a reduction reaction of compound 7p with SnCl 2 ·2H 2 O was used to yield compound 7s that was reacted with methanesulfonyl chloride to afford compound 7t 36 . As shown in Scheme 4, compound 7q or 7r was treated with methanesulfonyl chloride to achieve compound 7u or 7w 37 and was reacted with 1‐(fluorosulfonyl)−2,3‐dimethyl‐1H‐imidazol‐3‐ium trifluoromethanesulfonate to yield compound 7v or 7x , 38 respectively.…”

Section: Resultsmentioning

confidence: 99%

Discovery of low‐molecular‐weight phenylalanine derivatives as novel HIV capsid modulators with improved antiretroviral activity and metabolic stability

Jiang,

Gao,

Sharma

et al. 2024

Journal of Medical Virology

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The HIV capsid (CA) protein is a promising target for anti‐AIDS treatment due to its critical involvement in viral replication. Herein, we utilized the well‐documented CA inhibitor PF74 as our lead compound and designed a series of low‐molecular‐weight phenylalanine derivatives. Among them, compound 7t exhibited remarkable antiviral activity with a high selection index (EC50 = 0.040 µM, SI = 2815), surpassing that of PF74 (EC50 = 0.50 µM, SI = 258). Furthermore, when evaluated against the HIV‐2 strain, 7t (EC50 = 0.13 µM) demonstrated approximately 14‐fold higher potency than that of PF74 (EC50 = 1.76 µM). Insights obtained from surface plasmon resonance (SPR) revealed that 7t exhibited stronger target affinity to the CA hexamer and monomer in comparison to PF74. The potential interactions between 7t and the HIV‐1 CA were further elucidated using molecular docking and molecular dynamics simulations, providing a plausible explanation for the enhanced target affinity with 7t over PF74. Moreover, the metabolic stability assay demonstrated that 7t (T1/2 = 77.0 min) significantly outperforms PF74 (T1/2 = 0.7 min) in human liver microsome, exhibiting an improvement factor of 110‐fold. In conclusion, 7t emerges as a promising drug candidate warranting further investigation.

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Section: Resultsmentioning

confidence: 99%

Discovery of low‐molecular‐weight phenylalanine derivatives as novel HIV capsid modulators with improved antiretroviral activity and metabolic stability

Jiang,

Gao,

Sharma

et al. 2024

Journal of Medical Virology

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“…The target inhibitor, 3-((4-(4-cyano-2,6-dimethylphenoxy)thieno [3,2-d]pyrimidin-2yl)amino)phenyl sulfurofluoridate, which has a fluorosulfate warhead, was reported to be a strong inhibitor (EC 50 = 11-246 nM) against HIV-1 IIIB and a panel of NNRTI-resistant strains, considerably outperforming NVP and EFV, and displayed decreased cytotoxicity (CC 50 = 125 µM). The compound had an IC 50 value of 0.057 µM in the reverse transcriptase inhibitory experiment using the ELISA technique, and the MALDI-TOF MS data indicated ZA-2's covalent binding mode with the enzyme [89].…”

Section: Targeting Highly Hydrophobic Channelsmentioning

confidence: 94%

Strategies in the Design and Development of Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

Vanangamudi,

Palaniappan,

Kathiravan

et al. 2023

Viruses

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AIDS (acquired immunodeficiency syndrome) is a potentially life-threatening infectious disease caused by human immunodeficiency virus (HIV). To date, thousands of people have lost their lives annually due to HIV infection, and it continues to be a big public health issue globally. Since the discovery of the first drug, Zidovudine (AZT), a nucleoside reverse transcriptase inhibitor (NRTI), to date, 30 drugs have been approved by the FDA, primarily targeting reverse transcriptase, integrase, and/or protease enzymes. The majority of these drugs target the catalytic and allosteric sites of the HIV enzyme reverse transcriptase. Compared to the NRTI family of drugs, the diverse chemical class of non-nucleoside reverse transcriptase inhibitors (NNRTIs) has special anti-HIV activity with high specificity and low toxicity. However, current clinical usage of NRTI and NNRTI drugs has limited therapeutic value due to their adverse drug reactions and the emergence of multidrug-resistant (MDR) strains. To overcome drug resistance and efficacy issues, combination therapy is widely prescribed for HIV patients. Combination antiretroviral therapy (cART) includes more than one antiretroviral agent targeting two or more enzymes in the life cycle of the virus. Medicinal chemistry researchers apply different optimization strategies including structure- and fragment-based drug design, prodrug approach, scaffold hopping, molecular/fragment hybridization, bioisosterism, high-throughput screening, covalent-binding, targeting highly hydrophobic channel, targeting dual site, and multi-target-directed ligand to identify and develop novel NNRTIs with high antiviral activity against wild-type (WT) and mutant strains. The formulation experts design various delivery systems with single or combination therapies and long-acting regimens of NNRTIs to improve pharmacokinetic profiles and provide sustained therapeutic effects.

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Deciphering the enigmas of non‐nucleoside reverse transcriptase inhibitors (NNRTIs): A medicinal chemistry expedition towards combating HIV drug resistance

Zhang,

et al. 2024

Medicinal Research Reviews

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The pivotal involvement of reverse transcriptase activity in the pathogenesis of the progressive HIV virus has stimulated gradual advancements in drug discovery initiatives spanning three decades. Consequently, nonnucleoside reverse transcriptase inhibitors (NNRTIs) have emerged as a preeminent category of therapeutic agents for HIV management. Academic institutions and pharmaceutical companies have developed numerous NNRTIs, an essential component of antiretroviral therapy. Six NNRTIs have received Food and Drug Administration approval and are widely used in clinical practice, significantly improving the quality of HIV patients. However, the rapid emergence of drug resistance has limited the effectiveness of these medications, underscoring the necessity for perpetual research and development of novel therapeutic alternatives. To supplement the existing literatures on NNRTIs, a comprehensive review has been compiled to synthesize this extensive dataset into a comprehensible format for the medicinal chemistry community. In this review, a thorough investigation and meticulous analysis were conducted on the progressions achieved in NNRTIs within the past 8 years (2016–2023), and the experiences and insights gained in the development of inhibitors with varying chemical structures were also summarized. The provision of a crucial point of reference for the development of wide‐ranging anti‐HIV medications is anticipated.

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Covalently Targeted Highly Conserved Tyr318 to Improve the Drug Resistance Profiles of HIV-1 NNRTIs: A Proof-of-Concept Study

Cited by 4 publications

References 23 publications

Discovery of low‐molecular‐weight phenylalanine derivatives as novel HIV capsid modulators with improved antiretroviral activity and metabolic stability

Discovery of low‐molecular‐weight phenylalanine derivatives as novel HIV capsid modulators with improved antiretroviral activity and metabolic stability

Strategies in the Design and Development of Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

Deciphering the enigmas of non‐nucleoside reverse transcriptase inhibitors (NNRTIs): A medicinal chemistry expedition towards combating HIV drug resistance

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