Recent progress in the discovery of macrocyclic compounds as potential anti-infective therapeutics.

Novel therapeutic strategies are urgently needed for the treatment of serious diseases caused by viral, bacterial and parasitic infections, because currently used drugs are facing the problem of rapidly emerging resistance. There is also an urgent need for agents that act on novel pathogen-specific targets, in order to expand the repertoire of possible therapies. The high throughput screening of diverse small molecule compound libraries has provided only a limited number of new lead series, and the number of compounds acting on novel targets is even smaller. Natural product screening has traditionally been very successful in the anti-infective area. Several successful drugs on the market as well as other compounds in clinical development are derived from natural products. Amongst these, many are macrocyclic compounds in the 1-2 kDa size range. This review will describe recent advances and novel drug discovery approaches in the anti-infective area, focusing on synthetic and natural macrocyclic compounds for which in vivo proof of concept has been established. The review will also highlight the Protein Epitope Mimetics (PEM) technology as a novel tool in the drug discovery process. Here the structures of naturally occurring antimicrobial and antiviral peptides and proteins are used as starting points to generate novel macrocyclic mimetics, which can be produced and optimized efficiently by combinatorial synthetic methods. Several recent examples highlight the great potential of the PEM approach in the discovery of new anti-infective agents.

Exploiting conformationally constrained peptidomimetics and an efficient human-compatible delivery system in synthetic vaccine design.

Peptide and protein mimetics are potentially of great value in synthetic vaccine design. The mimetics should function by stimulating the immune system to produce antibodies that recognize the intact parasite. Also the mimetics should be presented to the immune system in a way that leads to efficient antibody production. Here we investigate the application of cyclic peptidomimetics presented on immunopotentiating reconstituted influenza virosomes (IRIVs), a form of antigen delivery that is licensed already for human clinical use, in synthetic vaccine design. We focus on the central (NPNA)(n) repeat region of the circumsporozoite (CS) protein of the malaria parasite Plasmodium falciparum as a model system. Cyclic peptidomimetics of the NPNA repeats were incorporated into both an IRIV and (for comparison) a multiple-antigen peptide (MAP). Both IRIV and MAP delivery forms induced mimetic-specific humoral immune responses in mice, but only with the mimetic-IRIV preparations did a significant fraction of the elicited antibodies cross-react with sporozoites. The results demonstrate that IRIVs are a delivery system suitable for the efficient induction of antibody responses against conformational epitopes by use of cyclic template-bound peptidomimetics. Combined with combinatorial chemistry, this approach may have great potential for the rapid optimization of molecularly defined synthetic vaccine candidates against a wide variety of infectious agents.

Peptides and peptoids--a quantum chemical structure comparison.

Peptoids represent a very interesting structure alternative to peptides. Based on ab initio MO theory employing the 6-31G* and 3-21G basis sets and considering correlation energy, a systematic structure comparison between the basic structure units of peptoids and peptides is performed. The calculations show three minimum conformations denoted as C7 beta, alpha D, and alpha that do not correspond to conformers on the peptide potential energy hypersurface. The possibility of cis peptide bonds in the peptoids was examined. The solvent influence on the structure was estimated by means of various quantum chemical continuum models.

Models of aging and neuropsychological test performance decline with aging.

While some researchers have claimed that normal aging need not be accompanied by significant neuropsychological deficits ("preserved function" models), others have asserted that aging is associated with significant deficits in either specific or general cognitive functioning ("specific" vs "general" decline models). Among the significant decline models, there is disagreement regarding which functions are affected and to what degree, and at what point in the normal life span such a decline becomes significant. This study examined the neuropsychological test performance of 86 adults with no objective evidence of brain dysfunction. Significant decline, beginning as early as the 30s or 40s, was seen on all measures except the simple motor task of finger tapping. These results are viewed as supporting a model of differential decline of specific functions nested within a general decline model.

Statistical and diagnostic adequacy of a short form of the Halstead Category Test.

The current study examined the statistical adequacy of shortened versions (SF) of the Halstead Category Test (CT) through several multiple regression analyses (MRA), using a large sample (N = 1012) of neurologically- referred patients to allow for reasonable confidence in the reliability of the findings. The diagnostic accuracy of the psychometrically soundest short form (consisting of subtests 4, 6, and 3) was then compared to that of the long form on a subsample of 590 patients from the first study for whom brain damage had either been medically confirmed or ruled out. Results suggest that a short form may be psychometrically feasible, with little loss in diagnostic accuracy.

Laterality of brain damage and emotional disturbance in adults.

Although there has been agreement that brain injury often alters emotional functioning, there has been little agreement regarding the effects of lateralized brain injury on emotional status. The current study examined a fairly large sample of lateralized brain injured patients (N = 186) and compared scores on an objective self-report measure of personality or emotional status (MMPI). Results are consistent with prior studies by Reitan and others in that there were no significant differences between lateralized groups. Both groups showed moderate elevations (T scores in the low 60s) on scales 1, 2, 3, and 8. This was interpreted as reflecting somatic concern, mild-moderate depression, and interpersonal difficulties.

Academic achievement and intelligence test performance in children with cancer at diagnosis and one year later.

Recent investigations have found significant test-retest decline in certain academic achievement and intelligence test scores in children diagnosed as having acute lymphocytic leukemia (ALL) before 8 years of age. No such effect was observed in children diagnosed at or later than age 8 years. The current study, using a sample of 77 children with ALL, failed to support these findings. No significant differences were found between groups at test or retest nor were significant declines seen for either group from test to retest 1 year later. Reasons for differences in findings between studies, including methodological and samples size differences, are discussed along with implications for future research in this area.

Statistical test of a short form of the speech-sounds perception test in a child population.

The adequacy of a shortened version of the children's Speech-Sounds Perception Test was examined. In two different groups of chronically ill children, stepwise multiple regression analysis demonstrated that the first three subtests (first 30 items) accounted for over 87% of the variance in the total 60-item test. The 30-item version appears to be as useful with children as the full 60-item test.

The relationship between neuropsychological functioning and psychopathology in temporal lobe epileptic patients.

With the use of Goldberg's method of Minnesota Multiphasic Personality Inventory (MMPI) analysis, evidence has been recently provided of a positive relationship between psychopathology and deficits in neuropsychological functioning in epileptic patients. The present study attempted to replicate this finding using more precise and appropriate criteria for grouping patients according to severity of neuropsychological impairment. Application of Goldberg's MMPI Rules to 34 temporal lobe epileptic patients grouped according to their neuropsychological status (nonimpaired or impaired) failed to support these findings. Possible reasons for the discrepant results, including differing methodologies and seizure patient characteristics across studies, are discussed.

Assessment of level of consciousness following severe neurological insult. A comparison of the psychometric qualities of the Glasgow Coma Scale and the Comprehensive Level of Consciousness Scale.

An alternative method of coma assessment is presented and compared with the Glasgow Coma Scale. The merits of the Comprehensive Level of Consciousness Scale as a research tool are presented. An analysis of 101 consecutive consciousness-impaired patients with their short-term outcome is presented.

Language-related skills in children with acute lymphocytic leukemia.

The success of cranial irradiation and chemotherapy in the treatment of acute lymphocytic leukemia (ALL) has raised concerns about possible central nervous system damage in long-term survivors. The current study focused on language-related skill measures obtained as part of a neuropsychological test battery. Performance was analyzed as a function of age at diagnosis and age at evaluation in a sample of 110 children with ALL (mean age = 13.28 years). Results, although for the most part nonsignificant, do reveal significantly poorer performance on an Aphasia Screening Test rating by those diagnosed early (at or before five years of age) and assessed at or before 13 years of age when contrasted with those diagnosed early and assessed after their thirteenth year. Further analysis revealed a significant decline in spelling scores for those off therapy for more than two years. There was also a consistent trend for decline across most language-related skills measures as time off therapy increased. These results reflect either recovery from mild acute language dysfunction over time superimposed on a general trend for decline in language-related skills as time off therapy increases, or sampling error. Suggestions for future lines of investigation are discussed.