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Semi-quantitative models for identifying potent and selective transthyretin amyloidogenesis inhibitors

Connelly, Stephen,Mortenson, David E.,Choi, Sungwook,Wilson, Ian A.,Powers, Evan T.,Kelly, Jeffery W.,Johnson, Steven M. Pergamon Press 2017 Bioorganic & medicinal chemistry letters Vol.27 No.15
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Abstract Rate-limiting dissociation of the tetrameric protein transthyretin (TTR), followed by monomer misfolding and misassembly, appears to cause degenerative diseases in humans known as the transthyretin amyloidoses, based on human genetic, biochemical and pharmacologic evidence. Small molecules that bind to the generally unoccupied thyroxine binding pockets in the native TTR tetramer kinetically stabilize the tetramer, slowing subunit dissociation proportional to the extent that the molecules stabilize the native state over the dissociative transition state—thereby inhibiting amyloidogenesis. Herein, we use previously reported structure-activity relationship data to develop two semi-quantitative algorithms for identifying the structures of potent and selective transthyretin kinetic stabilizers/amyloidogenesis inhibitors. The viability of these prediction algorithms, in particular the more robust in silico docking model, is perhaps best validated by the clinical success of tafamidis, the first-in-class drug approved in Europe, Japan, South America, and elsewhere for treating transthyretin aggregation-associated familial amyloid polyneuropathy. Tafamidis is also being evaluated in a fully-enrolled placebo-controlled clinical trial for its efficacy against TTR cardiomyopathy. These prediction algorithms will be useful for identifying second generation TTR kinetic stabilizers, should these be needed to ameliorate the central nervous system or ophthalmologic pathology caused by TTR aggregation in organs not accessed by oral tafamidis administration. Graphical abstract [DISPLAY OMISSION]
2
Nitrate-Containing Beetroot Juice Reduces Oxygen Consumption During Submaximal Exercise in Low but Not High Aerobically Fit Male Runners

( Colin R. Carriker ),( Roger A. Vaughan ),( Trisha A. Vandusseldorp ),( Kelly E. Johnson ),( Nicholas M. Beltz ),( James J. Mccormick ),( Nathan H. Cole ),( Ann L. Gibson ) 한국운동영양학회 2016 Physical Activity and Nutrition (Phys Act Nutr) Vol.20 No.4
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[Purpose] To examine the effect of a 4-day NO3- loading protocol on the submaximal oxygen cost of both low fit and high fit participants at five different exercise intensities. [Methods] Eleven (6 high fit, VO2max 60.1 ± 4.6ml/kg/min; 5 low fit, VO2max 42.4 ± 3.2ml/ kg/min) participants were initially assigned to a placebo (PL; negligible NO3-) or inorganic nitrate-rich (NR; 6.2 mmol nitrate/day) group using a double-blind, placebo-controlled, crossover design. Participants completed three trials (T1, T2 and T3). T1 included a maximal aerobic capacity (VO2max) treadmill test. A 6-day washout, minimizing nitrate consumption, preceded T2. Each of the four days prior to T2 and T3, participants consumed either PL or NR with the final dose 2.5 hours prior to exercise. A 14-day washout followed T2. T2 and T3 consisted of 5-minute submaximal treadmill bouts (45, 60, 70, 80 and 85% VO2max) determined during T1. [Results] Low fit nitrate-supplemented participants consumed less oxygen (p<0.05) at lower workloads (45% and 60% VO2max) compared to placebo trials; changes were not observed in high fit participants. The two lowest intensity workloads of 45 and 60% VO2max revealed the greatest correlation (r=0.54, p=0.09 and r=0.79, p<0.05; respectively) between VO2max and change in oxygen consumption. No differences were found between conditions for heart rate, respiratory exchange ratio or rating of perceived exertion for either fitness group. [Conclusion] Nitrate consumption promotes reduced oxygen consumption at lower exercise intensities in low fit, but not high fit males. Lesser fit individuals may receive greater benefit than higher fit participants exercising at intensities <60% VO2max.