Allosteric Inhibition of Factor XIIIa. Non-Saccharide Glycosaminoglycan Mimetics, but Not Glycosaminoglycans, Exhibit Promising Inhibition Profile

Factor XIIIa (FXIIIa) is a transglutaminase that catalyzes the last step in the coagulation process. Orthostery is the only approach that has been exploited to design FXIIIa inhibitors. Yet, allosteric inhibition of FXIIIa is a paradigm that may offer a key advantage of controlled inhibition over orthosteric inhibition. Such an approach is likely to lead to novel FXIIIa inhibitors that do not carry bleeding risks. We reasoned that targeting a collection of basic amino acid residues distant from FXIIIa’s active site by using sulfated glycosaminoglycans (GAGs) or non-saccharide GAG mimetics (NSGMs) would lead to the discovery of the first allosteric FXIIIa inhibitors. We tested a library of 22 variably sulfated GAGs and NSGMs against human FXIIIa to discover promising hits. Interestingly, although some GAGs bound to FXIIIa better than NSGMs, no GAG displayed any inhibition. An undecasulfated quercetin analog was found to inhibit FXIIIa with reasonable potency (efficacy of 98%). Michaelis-Menten kinetic studies revealed an allosteric mechanism of inhibition. Fluorescence studies confirmed close correspondence between binding affinity and inhibition potency, as expected for an allosteric process. The inhibitor was reversible and at least 9-fold- and 26-fold selective over two GAG-binding proteins factor Xa (efficacy of 71%) and thrombin, respectively, and at least 27-fold selective over a cysteine protease papain. The inhibitor also inhibited the FXIIIa-mediated polymerization of fibrin in vitro. Overall, our work presents the proof-of-principle that FXIIIa can be allosterically modulated by sulfated non-saccharide agents much smaller than GAGs, which should enable the design of selective and safe anticoagulants

Absolute-Magnitude Distributions and Light Curves of Stripped-Envelope Supernovae

The absolute visual magnitudes of three Type IIb, 11 Type Ib and 13 Type Ic supernovae (collectively known as stripped-envelope supernovae) are studied by collecting data on the apparent magnitude, distance, and interstellar extinction of each event. Weighted and unweighted mean absolute magnitudes of the combined sample as well as various subsets of the sample are reported. The limited sample size and the considerable uncertainties, especially those associated with extinction in the host galaxies, prevent firm conclusions regarding differences between the absolute magnitudes of supernovae of Type Ib and Ic, and regarding the existence of separate groups of overluminous and normal-luminosity stripped-envelope supernovae. The spectroscopic characteristics of the events of the sample are considered. Three of the four overluminous events are known to have had unusual spectra. Most but not all of the normal luminosity events had typical spectra. Light curves of stripped-envelope supernovae are collected and compared. Because SN 1994I in M51 was very well observed it often is regarded as the prototypical Type Ic supernova, but it has the fastest light curve in the sample. Light curves are modeled by means of a simple analytical technique that, combined with a constraint on E/M from spectroscopy, yields internally consistent values of ejected mass, kinetic energy, and nickel mass.Comment: 39 pages, 14 figures, 7 tables; Accepted to A