Development of non-nucleoside reverse transcriptase inhibitors (NNRTIs): our past twenty years.

Human immunodeficiency virus (HIV) is the primary infectious agent of acquired immunodeficiency syndrome (AIDS), and non-nucleoside reverse transcriptase inhibitors (NNRTIs) are the cornerstone of HIV treatment. In the last 20 years, our medicinal chemistry group has made great strides in developing several distinct novel NNRTIs, including 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT), thio-dihydro-alkoxy-benzyl-oxopyrimidine (S-DABO), diaryltriazine (DATA), diarylpyrimidine (DAPY) analogues, and their hybrid derivatives. Application of integrated modern medicinal strategies, including structure-based drug design, fragment-based optimization, scaffold/fragment hopping, molecular/fragment hybridization, and bioisosterism, led to the development of several highly potent analogues for further evaluations. In this paper, we review the development of NNRTIs in the last two decades using the above optimization strategies, including their structure-activity relationships, molecular modeling, and their binding modes with HIV-1 reverse transcriptase (RT). Future directions and perspectives on the design and associated challenges are also discussed.

Improving the positional adaptability: structure-based design of biphenyl-substituted diaryltriazines as novel non-nucleoside HIV-1 reverse transcriptase inhibitors.

In order to improve the positional adaptability of our previously reported naphthyl diaryltriazines (NP-DATAs), synthesis of a series of novel biphenyl-substituted diaryltriazines (BP-DATAs) with a flexible side chain attached at the C-6 position is presented. These compounds exhibited excellent potency against wild-type (WT) HIV-1 with EC50 values ranging from 2.6 to 39 nmol/L and most of them showed low nanomolar anti-viral potency against a panel of HIV-1 mutant strains. Compounds 5j and 6k had the best activity against WT, single and double HIV-1 mutants and reverse transcriptase (RT) enzyme comparable to two reference drugs (EFV and ETR) and our lead compound NP-DATA (1). Molecular modeling disclosed that the side chain at the C-6 position of DATAs occupied the entrance channel of the HIV-1 reverse transcriptase non-nucleoside binding pocket (NNIBP) attributing to the improved activity. The preliminary structure-activity relationship and PK profiles were also discussed.

The effect of maternal HIV status and treatment duration on body composition of HIV-exposed and HIV-unexposed preterm, very and extremely low-birthweight infants.

BACKGROUND: There is an evidence gap regarding the relationship between HIV exposure, body composition (and the quality thereof) and preterm infants. AIM: This study determined the body composition of HIV-exposed, preterm very low-birthweight (VLBW) and extremely low-birthweight (ELBW) infants and to assess the effect of maternal HAART duration on the body composition of this vulnerable population. METHODS: A descriptive cross-sectional study was conducted. HIV-exposed and -unexposed preterm infants (<37 weeks) with a birthweight of ≤1200g were included. Maternal medical background was recorded. Infant body composition measurements were recorded weekly during the 28-day follow-up period. RESULTS: Thirty preterm infants (27%) were HIV-exposed. HIV-exposed infants had significantly (=0.01) lower gestational ages than HIV-unexposed infants (25-28 weeks). HIV-exposed infants had significantly lower measurements on day 21 and day 28 for triceps skinfold (TSF) (2.5 mm vs 2.7 mm, = 0.02 and 2.6 mm vs 2.9 mm, <0.01), subscapular skinfold (SSSF) (2.3 mm vs 2.6 mm, = 0.02 and 2.4 mm vs 2.7 mm, =<0.01) and fat mass percentage (FM%) (0.9% vs 1.4%, = 0.02 and 1.0% vs 1.5%, = 0.03). HIV-exposed infants whose mothers received HAART for ≥ 20 weeks were heavier and had a higher FM% and lower fat-free mass percentage (FFM%) at birth than HIV-exposed preterm infants whose mothers received highly active antiretroviral therapy for ≥ 4- < 20 weeks. CONCLUSION: Mothers receiving HAART could have increased risk of preterm delivery, and the duration of maternal HAART affects postnatal body composition of their infants. Body composition differs between HIV-exposed and HIV-unexposed preterm infants.

Insights into CYP2B6-mediated drug-drug interactions.

Mounting evidence demonstrates that CYP2B6 plays a much larger role in human drug metabolism than was previously believed. The discovery of multiple important substrates of CYP2B6 as well as polymorphic differences has sparked increasing interest in the genetic and xenobiotic factors contributing to the expression and function of the enzyme. The expression of CYP2B6 is regulated primarily by the xenobiotic receptors constitutive androstane receptor (CAR) and pregnane X receptor (PXR) in the liver. In addition to CYP2B6, these receptors also mediate the inductive expression of CYP3A4, and a number of important phase II enzymes and drug transporters. CYP2B6 has been demonstrated to play a role in the metabolism of 2%-10% of clinically used drugs including widely used antineoplastic agents cyclophosphamide and ifosfamide, anesthetics propofol and ketamine, synthetic opioids pethidine and methadone, and the antiretrovirals nevirapine and efavirenz, among others. Significant inter-individual variability in the expression and function of the human CYP2B6 gene exists and can result in altered clinical outcomes in patients receiving treatment with CYP2B6-substrate drugs. These variances arise from a number of sources including genetic polymorphism, and xenobiotic intervention. In this review, we will provide an overview of the key players in CYP2B6 expression and function and highlight recent advances made in assessing clinical ramifications of important CYP2B6-mediated drug-drug interactions.

Changing incidence of nevirapine-induced cutaneous drug reactions: After revised guideline Nov 2011.

AIMS AND OBJECTIVES: To study the change in the incidence and pattern of nevirapine (NVP)-induced adverse cutaneous reactions (ADR) after commencement of revised National AIDS Control Organisation (NACO) guidelines for initiation of antiretroviral therapy (ART) since Nov 2011. MATERIALS AND METHODS: The study was conducted on patients who developed cutaneous reactions after starting NVP based regimen. According to the revised NACO ART initiation guidelines Nov 2011, ART should be started if CD4 count is < 350 cells/mm(3) in stages 1, and 2 and irrespective of CD4 count in stages 3, and 4. Patients were divided in groups A and B. Group A consisted of patients enrolled on NVP-based regimen during Jan 2011 to Oct 2011, whereas, in Group B patients from Nov 2011 to Aug 2012 were included. Grading of rash, appropriate investigations and management was done. OBSERVATIONS: In Group A, out of 645 patients 30 (4.66%) patients developed cutaneous reactions, where as in Group B out of 720, 65 (9.03%) patients presented with drug reaction. In Group A (n = 30) developed reaction as Grade 1 in 1.55% (n = 10), Grade 2 in 1.86% (n = 12), grades 3 and 4 in 0.76% (n = 5) and 0.47% (n = 3), respectively. In Group B (n = 65) developed reaction, out of which Grade 1 reaction was seen in 1.39% (n = 10), Grade 2 was seen in 2.78% (n = 20), grades 3 and 4 was seen in 3.33% (n = 24) and, 1.53% (n = 11), respectively. CONCLUSION: There is a striking increase in the incidence of NVP-induced cutaneous reactions of all forms and considerable increase in frequency of severe kind of reactions with the revised guidelines.