Microreactors for chemical synthesis.

The advances of the past few years in microreactors have demonstrated that the miniaturization of chemistry has significant advantages with respect to cost, safety, throughput, kinetics and scale-up. The use of chemical microreactors for catalytic oxidations, heterocyclic syntheses and photochemical reactions has illustrated the utility and benefits for both chemical discovery and chemical development applications.

The impact of polystyrene resins in solid-phase organic synthesis.

A major objective of the DIVERSOMER technology is to provide pure and characterized compounds for biological testing in order to prevent 'false negatives' in our libraries. On several occasions, analysis of the final products by 1H-NMR and MS, has revealed by-products from the polystyrene solid support. Subsequently, three alternative methods were studied to remove polystyrene by-products; (i) prewashing of the resin prior to execution of the synthesis; (ii) pretreatment of the resin with the cleavage conditions consistent with the solid-phase synthesis reaction scheme; and (iii) parallel purification.

Semen alloantigens and lymphocytotoxic antibodies in AIDS and ICL.

More than 90% of people with AIDS develop circulating immune complexes (CICs) and lymphocytotoxic antibodies (LCTAs). Animals infected with HIV, however, never display CICs or LCTAs, and remain healthy. Similarly, HIV-infected people who do not develop CICs or LCTAs also do not progress to AIDS. The appearance of CICs and LCTAs is, however, highly prognostic for AIDS and death. Since HIV infection does not, per se, lead to the development of CICs and LCTAs, other causes are likely. One such cause, for which both epidemiologic and experimental evidence exists, is semen. Semen components include sperm, seminal fluid, lymphocytes, and sometimes infectious agents, including HIV, mycoplasmas, and herpes and hepatitis viruses, all of which independently cause immune suppression. Extensive evidence demonstrates sperm (and various viruses) contains many proteins mimicking the CD4 protein of T-helper cells, while HIV, mycoplasmas, and seminal fluid mimic class II MHC proteins of other lymphocytes. We identify a large number of protein sequences that display such mimicry using computer homology searching, and demonstrate experimentally that sperm antibodies specifically precipitate antibodies against class II MHC mimics such as mycoplasmas, which in turn precipitate antibodies to lymphocyte antigens. These data prove that immunologic exposure to sperm and lymphocytes (as may occur in receptive anal intercourse, needle sharing, or blood transfusions) is theoretically capable of initiating lymphocytotoxic autoimmunity. Such autoimmunity may play a significant role in the pathogenesis of AIDS, and will need to be addressed clinically in high risk individuals regardless of HIV status and regardless of the success of anti-HIV prophylaxis and treatment.

CD4 similarity to proteins of infectious agents in AIDS and their role in autoimmunity.

Lymphocytotoxic autoimmunity (LA) is ubiquitous in AIDS. Its causes are unknown. We report that significant amino acid sequence similarities exist between the proteins of infectious organisms associated with AIDS and the CD4 protein of T-helper lymphocytes. These included: HIV, cytomegalovirus (CMV), Epstein-Barr virus (EBV), herpes simplex viruses (HSV), Varicella Zoster virus (VZV), Escherichia coli, Mycobacteria, Mycoplasmas, Plasmodium, and Staphylococcus. It has been reported previously that HIV proteins have significant similarities with human class II MHC (HLA class II) proteins. Since CD4 and HLA class II proteins are chemically complementary, pairs of homologous antigens will also be complementary. It follows that concurrent infections with CD4 and HLA class II-homologous antigens will result in idiotype-antiidiotype antibody pairs that cannot distinguish 'self' from 'nonself', that acts as lymphocytotoxins, and form circulating immune complexes. Thus, combined HIV-CMV, HIV-EBV, HIV-HBV, HIV-mycoplasma, or other appropriate infectious pairs may suffice to trigger LA in AIDS.

"Diversomers": an approach to nonpeptide, nonoligomeric chemical diversity.

Solid-phase chemistry, organic synthesis, and an apparatus for multiple, simultaneous synthesis have been combined to generate libraries of organic compounds ("diversomers"). Arrays of compounds were synthesized over two to three steps incorporating chemically diverse building blocks on a polystyrene-based solid support in a multiple, simultaneous manner. The generality of this approach is illustrated by the syntheses of dipeptides, hydantoins, and benzodiazepines.