Veterinary trypanocidal benzoxaboroles are peptidase-activated prodrugs.

Livestock diseases caused by Trypanosoma congolense, T. vivax and T. brucei, collectively known as nagana, are responsible for billions of dollars in lost food production annually. There is an urgent need for novel therapeutics. Encouragingly, promising antitrypanosomal benzoxaboroles are under veterinary development. Here, we show that the most efficacious subclass of these compounds are prodrugs activated by trypanosome serine carboxypeptidases (CBPs). Drug-resistance to a development candidate, AN11736, emerged readily in T. brucei, due to partial deletion within the locus containing three tandem copies of the CBP genes. T. congolense parasites, which possess a larger array of related CBPs, also developed resistance to AN11736 through deletion within the locus. A genome-scale screen in T. brucei confirmed CBP loss-of-function as the primary mechanism of resistance and CRISPR-Cas9 editing proved that partial deletion within the locus was sufficient to confer resistance. CBP re-expression in either T. brucei or T. congolense AN11736-resistant lines restored drug-susceptibility. CBPs act by cleaving the benzoxaborole AN11736 to a carboxylic acid derivative, revealing a prodrug activation mechanism. Loss of CBP activity results in massive reduction in net uptake of AN11736, indicating that entry is facilitated by the concentration gradient created by prodrug metabolism.

Identification of a 4-fluorobenzyl l-valinate amide benzoxaborole (AN11736) as a potential development candidate for the treatment of Animal African Trypanosomiasis (AAT).

Novel l-valinate amide benzoxaboroles and analogues were designed and synthesized for a structure-activity-relationship (SAR) investigation to optimize the growth inhibitory activity against Trypanosoma congolense (T. congolense) and Trypanosoma vivax (T. vivax) parasites. The study identified 4-fluorobenzyl (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbonyl)-l-valinate (5, AN11736), which showed IC50 values of 0.15 nM against T. congolense and 1.3 nM against T. vivax, and demonstrated 100% efficacy with a single dose of 10 mg/kg against both T. congolense and T. vivax in mouse models of infection (IP dosing) and in the target animal, cattle, dosed intramuscularly. AN11736 has been advanced to early development studies.

Spectral Parameters of HRV In Yoga Practitioners, Athletes And Sedentary Males.

Physical inactivity is an important risk factor for cardiovascular mortality and morbidity. Exercise is considered an acceptable method for improving and maintaining physical and emotional health. Although yoga is historically a spiritual discipline, a growing body of evidence supports the belief that yoga benefits physical and mental health. The objective of this study was to evaluate heart rate variability which reflects autonomic control of heart among yoga practitioners, athletes and individuals with sedentary lifestyle. The study was carried out in the departments of physiology at MAMC Agroha, Hisar and Pt. BD Sharma PGIMS Rohtak, Haryana. The study group comprised of 1200 healthy male volunteers of 16 to 55 years of age. The study group was divided into four age groups: Group A of age 16 to 25 years; Group B of age 26 to 35 years; Group C of age 36 to 45 years and Group D of age 46 to 55 years. All age groups were further divided into three categories i.e athlete (runner), yoga (yoga practitioners) and sedentary in which individuals with sedentary life style were included. The basal recording of ECG in lead II was done for 5 minutes. The Polyrite-D ECG data was used for analysis of heart rate variability by frequency domain method. Two spectral components were recorded namely high frequency (HF) component (0.15-0.4 Hz), an indicator of vagal efferent activity and low frequency (LF) component (0.04-.15 Hz), replicator of composite sympatho-vagal interplay. HF component in normalized unit was found significantly high in age group B and C in yoga practitioners and athletes as compared to sedentary individuals and in age group D significantly high in yoga practitioners as compared to athletes and sedentary individuals. Significantly decreased LF/HF ratio was found in age group B and C in yoga and athlete subjects as compared to sedentary individuals and in age group D in yoga practitioners as compared to athletes and sedentary individuals. This indicates that parasympathetic activity is substantially greater in yoga practitioners.