The first function of the epidermis is to form a barrier between the external environment and the internal medium. It is the outermost layer of the epidermis, the stratum corneum, which carries out this task. It is formed of keratinocytes at the final stage of their differentiation: corneocytes, which are cemented to one another by a thick intercellular cement which is both flexible and impermeable. This physical barrier which is the skin makes it possible for the human body to protect itself against numerous types of attack. These attacks can have different intrinsic origins, such as chronological aging or else biochemical changes which take place during states of fatigue, stress or hormonal changes such as those during pregnancy, etc. Other attacks are extrinsic in origin, such as pollution, the sun, disease, etc. In response to these attacks, the appearance of the skin is changed and the appearance of wrinkles and fine lines, areas of hyper- or hypopigmentation, dryness or even dehydration of the skin, a thinning of the epidermis, elastosis, imperfections, aged areas, etc. is observed. These changes are caused by the alteration to the functions of cellular renewal, cellular cohesion and synthesis of collagen, elastin and other proteins, and ultimately lead to a decrease in the protective barrier qualities of the skin and to a less attractive appearance thereof.
Like all the other organs, the skin is subjected to the influence of periodic variations. It represents the head office of a coherent organization of circadian and nycthemeral rhythms which modulate various, usually large-scale, biological cycles (F. Henry et al., Rev Med Liege; 57:10:661-665). In humans, these cutaneous rhythms suggest that, during the day, the skin promoted various protective functions with regard to the environment. During the evening and night, it promotes its cellular renewal and various metabolic synthesis processes.
In a subject in good health, where the organism lives in harmony with its environment, the biological rhythms are synchronised. By contrast, disturbances to the biological rhythms may appear in a certain number of conditions called ‘desynchronization’ (Reinberg and Touitou, 1996). Desynchronization is a state in which two (or more) rhythmic variables, which were previously synchronised, no longer have the same frequency and/or acrophase relations and exhibit temporal relations which are different to usual relations. Desynchronization may be of external origin, and thus depends on environmental changes and occurs, for example, during a transmeridian flight passing through five time zones (‘jet lag’) or when working through the night. Desynchronization on internal origin does not depend of environmental factors. It occurs with aging or with a certain number of illnesses, such as depression or some cancers. These problems of desynchronization can be corrected by various treatments: for example the administration of strong light in order to treat seasonal depression, or else the administration of melatonin (Dijk et coll., 1995; Eastman et Miescke, 1990; Palm et coll., 1992; Schochat et coll., 1998; Touitou et coll., 1998). In cosmetics, it is well known that the efficacy of a treatment can be optimized in accordance with the time of day at which it is administered. For example, day creams make it possible to protect the skin against external attacks during the day, whereas night creams enable the skin to repair any damage incurred during the day by increasing cellular renewal and metabolism. Furthermore, it has been demonstrated that aging is accompanied by a change in the biological rhythms, with a decrease in amplitude and a tendency towards phase lead (Weinert D., Chronobiol. Int. 2000; 17:261-83). Moreover, it has been shown that the circadian clock was altered by this same aging process. However, no treatment currently makes it possible for the skin to ‘re-start’ or else revive its circadian cycle, or to resynchronize its biological clock. Such a treatment would thus make it possible to help the skin to recover from a time difference, night-time work, or else to fight against signs caused by aging.
Surprisingly, the applicant has discovered that peptide compounds of the following general formula R1-(AA)n-X1-Ser-Thr-Pro-X2-(AA)p-R2 have the property of restoring the circadian rhythm and resynchronising the biological clock of skin cells. No document of the prior art describes such peptide compounds in order to obtain such effects. Furthermore, these peptide compounds are characterized by the fact that they are activator agents, either directly or indirectly, of the Clock (circadian locomotor output cycles kaput) protein involved in the regulation of the circadian cycle. Consequently, the present invention relates to peptide compounds which are Clock activators and to their use in cosmetic and pharmaceutical compositions in order to restore the circadian rhythm and resynchronize the biological clock of skin cells or else prevent or correct the signs caused by aging.
It has long been known that the circadian clock is controlled by a negative regulation loop involving a set of genes, in particular the Per-1 (period), Clock and BMAL-1 (brain and muscle ARNt-like protein) genes. Previously, in the prior art, numerous applications have already been proposed with regard to the use of nucleotides and/or proteins produced by Clock, Per-1 or BMAL-1 genes. For example, see U.S. Pat. No. 6,291,429 which describes the use of the product of the Clock gene to resynchronize the sleep cycle or physiological or endocrinal processes, or to resynchronize the body after jet lag, etc. However, no document of the prior art describes the use of specific Clock activator peptides in order to restore the skin's internal biological clock.