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Cathepsin S has been of increasing interest as a target of medicinal chemistry efforts given its role in modulating antigen-presentation by major histocompatibility class II (MHC II) molecules as well as its involvement in extracellular proteolytic activities. Inhibition of the cathepsin S enzyme reduces degradation of the invariant chain, a crucial chaperon which also blocks peptide-binding by MHC II molecules, thereby decreasing antigen presentation to CD4 T-cells. Extracellular cathepsin S may also be involved in angiogenesis and initiation and/or maintenance of neuropathic pain by cleavage of the membrane-bound chemokine fractalkine (CX3CL1). Cathepsin S inhibitors have thus been suggested to hold potential as therapeutics for a variety of diseases. The initial development of cathepsin S inhibitors targeted irreversible, covalent inhibitors, but more recently the focus has been on reversible inhibitors, representing both covalent modifiers of the enzyme and, of late, noncovalent inhibitors. This review details advances in cathepsin S inhibitor design as reported in the primary literature since 2006, focusing especially on structure-activity relationships of the various covalent and noncovalent inhibitor series.

Vaccination of man against epidemic influenza has given promising results in controlled studies during the past few years. Whereas earlier experiments yielded suggestive, equivocal or negative data, the development of vaccines prepared by various means from allantoic fluid infected with influenza virus led to the demonstration of definite protective effects by such preparations both under conditions of epidemic1 and experimental exposure of vaccinated persons to influenza virus.2 Thus the reports of the members of the Commission on Influenza of the Army Epidemiological Board indicated a reduction in the incidence of the disease of about 70 per cent in the influenza A epidemic of 19431 and of 90 to 95 per cent in the influenza B outbreak of 1945.3Encouraging as these results were, reservations had to be made because of proved antigenic differences between various strains of influenza viruses of either type. Such differences were readily