Identification of novel diarylpyrimidine derivatives as potent HIV-1 non-nucleoside reverse transcriptase inhibitors against wild-type and K103N mutant viruses

Article

Author: De Clercq, Erik ; Dai, Jiaojiao ; Ji, Xiangkai ; Jiang, Xiangyi ; Gao, Zhen ; Zhan, Peng ; Xie, Minghui ; Liu, Xinyong ; Huang, Boshi ; Zalloum, Waleed A. ; Zalloum, Waleed A ; Dong, Guanyu ; Pannecouque, Christophe

HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) play a crucial role in combination antiretroviral therapy (cART). To further enhance their antiviral activity and anti-resistance properties, we developed a series of novel NNRTIs, by specifically targeting tolerant region I of the NNRTI binding pocket. Among them, compound 9t-2 displayed excellent anti-HIV-1 potency against wild-type and prevalent mutant strains with EC₅₀ values between 0.0019 and 0.012 μM. This outperformed the positive drugs ETR, NVP and RPV. Aslo, ELISA results confirmed that these compounds can effectively inhibit the activity of HIV-1 RT. Molecular dynamics (MD) simulation studies indicated that the thiomorpholine-1,1-dioxide moiety of 9t-2 is capable of establishing additional interactions with residues P225, F227 and P236 in the tolerant region I, which contributed to its enhanced activity. Compound 9t-2 possessed negligible inhibitory effect on the five main CYP isoenzymes (IC₅₀ > 10 μM), indicating a low potential for inducing CYP-mediated drug-drug interactions. In conclusion, compound 9t-2, with its enhanced anti-resistance properties, stands out as a promising lead compound for further optimization towards discovering the new generation of anti-HIV agents.

14 Nov 2024·Journal of Medicinal Chemistry

Expanding the Solvent/Protein Region Occupation of the Non-Nucleoside Reverse Transcriptase Inhibitor Binding Pocket for Improved Broad-Spectrum Anti-HIV-1 Efficacy: from Rigid Phenyl-Diarylpyrimidines to Flexible Hydrophilic Piperidine-Diarylpyrimidines

Article

Author: Pannecouque, Christophe ; Corona, Angela ; Maloccu, Stefania ; Tramontano, Enzo ; Chen, Fen-Er ; De Clercq, Erik ; Huang, Wen-Juan ; Wang, Shuai

Considering the nonideal antiresistance efficacy of our previously reported non-nucleoside reverse transcriptase inhibitor 7, a series of novel piperidine-diarylpyrimidine derivatives were designed through expanding solvent/protein region occupation. The representative compound 15f proved to be exceptionally potent against Y188L (EC₅₀ = 23 nM), F227L + V106A (EC₅₀ = 15 nM) and RES056 (EC₅₀ = 45 nM), significantly better than 7. This analog exerted strong inhibition against wild-type HIV-1 (EC₅₀ = 3 nM) and single mutant strains (L100I, K103N, Y181C, E138 K). Notably, its cytotoxicity and selectivity (CC₅₀ = 18.23 μM, SI = 6537) were 4-fold better than etravirine and rilpivirine. Additionally, it exhibited minimal suppression of CYP isoenzymes and hERG, indicating low potential for drug-drug interactions and cardiotoxicity. No significant acute toxicity and tissue damage at a dose of 2 g/kg were revealed. These findings lay the groundwork for the advancement of 15f as a highly potent, safe, and broad-spectrum NNRTI for HIV therapy.

04 Nov 2024·Journal of Antimicrobial Chemotherapy

Real-world data on long-acting intramuscular maintenance therapy with cabotegravir and rilpivirine mirror Phase 3 results

Article

Author: Ghosn, Jade ; Peytavin, Gilles ; Phung, Bao-Chau ; Bachelard, Antoine ; Exarchopoulos, Marina ; Landman, Roland ; Yazdanpanah, Yazdan ; Charpentier, Charlotte ; Le Hingrat, Quentin ; Joly, Véronique ; Ferre, Valentine Marie ; Damond, Florence ; Serris, Alexandra ; Descamps, Diane

AbstractIntroductionCabotegravir, an integrase strand transfer inhibitor, and rilpivirine, an NNRTI, constitute the first long-acting (LA), injectable, two-drug ART regimen approved for the maintenance of virological suppression in persons living with HIV-1 (PLHIV). The aim of this study was to assess clinical effectiveness and tolerability of LA cabotegravir/rilpivirine in a real-world setting.Patients and methodsWe conducted a retrospective, single centre study, including all PLHIV receiving LA cabotegravir/rilpivirine as standard-of-care in our tertiary centre even if initiated in clinical trials.ResultsBetween 2014 and 2022, 126 PLHIV initiated LA cabotegravir/rilpivirine. All were ART-experienced, and 98.4% had a viral load (VL) of <50 copies/mL before LA cabotegravir/rilpivirine initiation. Median BMI at cabotegravir/rilpivirine initiation was 24 IQR (23–28). During a median follow-up of 9 months IQR (7–24), 27 patients discontinued cabotegravir/rilpivirine: 5 because of virological failure, 6 for adverse events, 11 for personal reasons unrelated to treatment tolerance and 5 for other reasons. Virological failure was not associated with a higher BMI, nor with weight gain during LA intramuscular (IM) cabotegravir/rilpivirine treatment, inadequate cabotegravir and rilpivirine concentrations, VL blips or the use of oral lead-in (OLI) or not. No drug resistance-associated mutation emerged. Adverse events leading to treatment interruption were injection-site pain (n = 3) and neuropsychological side effects (n = 3). A correlation between BMI and both cabotegravir and rilpivirine concentrations at 1 month post-initiation of LA-IM cabotegravir/rilpivirine was observed, with no impact of OLI.ConclusionsData from this real-world cohort of PLHIV who received cabotegravir/rilpivirine LA injections suggest that this regimen is effective and well tolerated. Virological failures were not associated with the acquisition of resistance mutations.

100 Deals associated with NNRTI (AiCuris)

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Indication	Highest Phase	Country/Location	Organization	Date
HIV Infections	Phase 1	DE	Aicuris Anti-Infective Cures AG	-

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


IAS2013	Not Applicable	HIV Infections	994	3-drug NVP-based	-	-	01 Jan 2013
				3-drug EFV-based
IAS2012	Not Applicable	Malaria \| HIV Infections	340	LPV/r-based ART	kxuwtduldn(hgcokejnmo) = vbfdsuvwia nfzsvlrzta (rkbyozddfr )	-	01 Jan 2012
				NNRTI-based ART	kxuwtduldn(hgcokejnmo) = lyvbcgzgjc nfzsvlrzta (rkbyozddfr )
IAS2010	Not Applicable	HIV Infections	64	PI-based combinations	ugavrovzej(oownvyfcgp) = yvhlmxovcf eefzenkjkj (vlsltxbqxz ) View more	-	01 Jan 2010
				NNRTI-based combinations	ugavrovzej(oownvyfcgp) = semtqourwv eefzenkjkj (vlsltxbqxz ) View more
IAS2008	Not Applicable	HIV Infections	350	NNRTI-based regimen (NVP or EFV)	jpynyechme(dusvkutwdd) = vhfvzqnzdx asfwsxedqh (smlcfgsbdb ) View more	-	01 Jan 2008
TASTE study (IAS2008)	Not Applicable	-	244	AZT/D4T+3TC+NNRTI/PI	qztxvuyssx(gkpnjiebvt) = 6 cases in the switch group nfrezjahzb (uvhtjpwsts ) View more	-	01 Jan 2008
				ABC+3TC+NNRTI/PI
IAS2007	Not Applicable	Cerebrospinal Fluid Leak	17	Tenofovir/emtricitabine + 1 NNRTI	tedrenhedv(zxrrqfaexi) = lehabfvitu rokajemzqt (tvtuwijgas ) View more	-	01 Jan 2007
IAS2007	Not Applicable	-	185	AZT/D4T+3TC+NNRTI/PI	xpcvdxuevt(xyubnjquvu) = rquigodanl zbctpgzzup (nhdtwlkfft ) View more	-	01 Jan 2007
				ABC+3TC+NNRTI/PI	xpcvdxuevt(xyubnjquvu) = qcjmtltafm zbctpgzzup (nhdtwlkfft ) View more

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