13437-63-3Relevant articles and documents
Exploring Structural Determinants of Inhibitor Affinity and Selectivity in Complexes with Histone Deacetylase 6
Osko, Jeremy D.,Porter, Nicholas J.,Narayana Reddy, Poli Adi,Xiao, You-Cai,Rokka, Johanna,Jung, Manfred,Hooker, Jacob M.,Salvino, Joseph M.,Christianson, David W.
, p. 295 - 308 (2020)
Inhibition of histone deacetylase 6 (HDAC6) has emerged as a promising therapeutic strategy for the treatment of cancer, chemotherapy-induced peripheral neuropathy, and neurodegenerative disease. The recent X-ray crystal structure determination of HDAC6 enables an understanding of structural features directing affinity and selectivity in the active site. Here, we present the X-ray crystal structures of five HDAC6-inhibitor complexes that illuminate key molecular features of the inhibitor linker and capping groups that facilitate and differentiate binding to HDAC6. In particular, aromatic and heteroaromatic linkers nestle within an aromatic cleft defined by F583 and F643, and different aromatic linkers direct the capping group toward shallow pockets defined by the L1 loop, the L2 loop, or somewhere in between these pockets. These results expand our understanding of factors contributing to the selective inhibition of HDAC6, particularly regarding interactions that can be targeted in the region of the L2 pocket.
Rational Design of Small Peptides for Optimal Inhibition of Cyclooxygenase-2: Development of a Highly Effective Anti-Inflammatory Agent
Singh, Palwinder,Kaur, Sukhmeet,Kaur, Jagroop,Singh, Gurjit,Bhatti, Rajbir
, p. 3920 - 3934 (2016/05/24)
Among the small peptides 2-31, (H)Gly-Gly-Phe-Leu(OMe) (30) reduced prostaglandin production of COX-2 with an IC50 of 60 nM relative to 6000 nM for COX-1. The 5 mg kg-1 dose of compound 30 rescued albino mice by 80% from capsaicin-induced paw licking and recovered it by 60% from carrageenan-induced inflammation. The mode of action of compound 30 for targeting COX-2, iNOS, and VGSC was investigated by using substance P, l-arginine, and veratrine, respectively, as biomarkers. The interactions of 30 with COX-2 were supported by isothermal calorimetry experiments showing a Ka of 6.10 ± 1.10 × 104 M-1 and ΔG of -100.3 kJ mol-1 in comparison to a Ka 0.41 × 103 ± 0.09 M-1 and ΔG of -19.2 ± 0.06 kJ mol-1 for COX-1. Moreover, compound 30 did not show toxicity up to a 2000 mg kg-1 dose. Hence, we suggest peptide 30 as a highly potent and promising candidate for further development into an anti-inflammatory drug.
METHOD FOR PRODUCING BIVALIRUDIN
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, (2012/01/13)
A method for producing bivalirudin using solid phase peptide synthesis by: a) condensing Fmoc-Asn(Trt)-Gly-OH with a peptide resin of Asp(OtBu)11-Phe12-Glu(OtBu)13-Glu(OtBu)14-Ile15-Pro16-Glu(OtBu)17-Glu(OtBu)18-Tyr(tBu)19-Leu20-Resin; b) removing Fmoc-; c) condensing Fmoc-Gly-Gly-Gly-Gly-OH with the peptide resin; d) separately condensing Pro, Arg, Pro, and Phe with the peptide resin from C-terminal to N-terminal to yield a peptide resin of Boc-D-Phe1-Pro2-Arg(Pbf)3-Pro4-Gly5-Gly6-Gly7-Gly8-Asn(Trt)9-Gly10-Asp(OtBu)11-Phe12-Glu(OtBu)13-Glu(OtBu)14-Ile15-Pro16-Glu(OtBu)17-Glu(OtBu)18-Tyr(tBu)19-Leu20-Resin; and e) in the presence of a cleavage agent, separating a peptide from the peptide resin to yield bivalirudin represented by Formula VI. The method is low in cost and the resultant bivalirudin has high purity.
