A study of the reactivity of S(VI)-F containing warheads with nucleophilic amino-acid side chains under physiological conditions.

Sulfonyl fluorides (SFs) have recently emerged as a promising warhead for the targeted covalent modification of proteins. Despite numerous examples of the successful deployment of SFs as covalent probe compounds, a detailed exploration of the factors influencing the stability and reactivity of SFs has not yet appeared. In this work we present an extensive study on the influence of steric and electronic factors on the reactivity and stability of the SF and related SVI-F groups. While SFs react rapidly with N-acetylcysteine, the resulting adducts were found to be unstable, rendering SFs inappropriate for the durable covalent inhibition of cysteine residues. In contrast, SFs afforded stable adducts with both N-acetyltyrosine and N-acetyllysine; furthermore, we show that the reactivity of arylsulfonyl fluorides towards these nucleophilic amino acids can be predictably modulated by adjusting the electronic properties of the warhead. These trends were largely conserved when the covalent reaction occurred within a protein binding pocket. We have also obtained a crystal structure depicting covalent modification of the catalytic lysine of a tyrosine kinase (FGFR1) by the ATP analog 5'-O-3-((fluorosulfonyl)benzoyl)adenosine (m-FSBA). Highly reactive warheads were demonstrated to be unstable with respect to hydrolysis in buffered aqueous solutions, indicating that warhead reactivity must be carefully tuned to provide optimal rates of protein modification. Our results demonstrate that the reactivity of SFs complements that of more commonly studied acrylamides, and we hope that this work spurs the rational design of novel SF-containing covalent probe compounds and inhibitors, particularly in cases where a suitably positioned cysteine residue is not present.

Climatic droplet keratopathy, exfoliation syndrome, and cataract.

During a countrywide survey we assessed the prevalence of climatic droplet keratopathy (CDK) in a randomised sample of 2446 subjects representative of the population of the Republic of Djibouti. The investigation of the relationship between CDK and two diseases considered to be related to exposure to ultra-violet light--namely, exfoliation syndrome and cataract--was planned as a case control study. In the rural area prevalence of CDK was five times higher than in the urban one (2.8% vs 0.5%) and varied according to districts. The highest rates were observed where the inhabitants' activities were related to the sea. The case control study revealed that the opacification of the lens was about three times commoner in patients with CDK than in patients without CDK (p = 0.03) and that the exfoliation syndrome was about six times commoner in patients with CDK than in controls of similar age, sex, climatic conditions, and lens status (p = 0.02). Moreover, we noticed that the sequelae of corneal perforations were about 30 times commoner in patients with CDK than in controls of similar age (p less than 0.00001).

[Corneal complications of climatic keratopathy]. / Complications cornéennes de la kératopathie de bietti.

The "keratopathie de Bietti" or climatic droplet keratopathy or keratopathie climatique (KC) is a degenerative disease of the cornea which is probably due to the exposure to ultraviolet rays. Usually the evolution is a progressive invasion of cornea by amber nodules which lift up the corneal epithelium. We observed that numerous patients suffered from severe corneal ulcerations which appeared to be spontaneous and which evolution was frequently disastrous. The aim of this work was to pick up epidemiologic data on KC in order to check the following hypothesis: the corneal opaquenesses, due to non traumatic perforations, would be more frequent among patients suffering from KC than among the rest of population. The study, carried out in Republic of Djibouti, dealed with two groups of people: an hospitable group of 217 patients suffering from a KC and a random sample of 2,446 persons among Djibouti people, from which a study ill-healthy was carried out among people from 40 years old. The mistakes were controled by adjustment on age and climatic conditions. The result is that corneal blindnesses which seemed to be spontaneous were more frequent in a significative way among people suffering from KC than among healthy people as old as ill people and living in the same conditions (12% against 0.7%; p = 0.003; Odds ratio adjusted on age: 31.8 IC: 8.8-115.20). On the etiopathogenic point of view the bacterial, fungal and deficiency causes could scarcely be accepted. The unfavourable evolution, resisting to all the treatments, drove to several hypothesis among them is responsibility of free amoebas as acanthamoeba.

[Epidemiological course of trachoma in Djibouti]. / Evolution de la situation épidémiologique du trachome a Djibouti.

A survey on a representative sample of population showed that inflammatory trachoma is rare in Republic of Djibouti. However, it is significatively more frequent in rural surroundings (0.4%, standard rates) than in urban surroundings (0.4%, standard rates) where it affects particularly people recently coming from border countries. In rural surroundings the frequency changes according to the distances from capital (p = 0.01). On the contrary, cicatricial trachoma is more frequent in the city (16.4%) than in rural surroundings (8.2%--Standard rates). The blindnesses caused by trachoma are relatively rare (0.1%) when entropiontrichiasis appear especially in urban surroundings (0.7%) where people from Arab Peninsula are the most affected (p = 0.008). When comparing with the 1968 situation, we notice a perceptible decrease of the prevalence of trachoma and also the disappearing of ethnic differences which existed at that time concerning the illness active forms. This good evolution is probably due to the effects of several mass campaigns added to an improvement of accessibility to medical care.