Inhibitor design by wrapping packing defects in HIV-1 proteins

Two viral proteins, HIV-1 protease and HIV-1 integrase, have been targeted for inhibitor design to prevent assembly and maturation of HIV-1 virions. The enzymatic mechanism of these proteins involves side-chain groups that serve as general acids or bases. Furthermore, catalytic activity requires that water be removed from the microenvironment surrounding the chemical reaction site or be constrained to serve as an activated nucleophile. Here, we identify previously unrecognized structural features that promote water removal from polar catalytic regions. Packing defects in the form of hydrogen bonds that are insufficiently dehydrated intramolecularly, named “dehydrons,” are strategically placed in the structure to induce an anhydrous enzymatic pathway. Dehydrons become electrostatically enhanced and stabilized upon further desolvation. Thus, packing defects act synergistically with the polar active groups to enhance the enzymatic electrostatics. However, because dehydrons are sticky, they constitute targets for inhibitor design. We noticed that inhibitors attach to polar surfaces by further desolvating dehydrons, thus blocking the active sites or the sites involved in harnessing the substrate. The dehydrons are thus required for functional reasons, making them suitable targets. The differences in success when targeting HIV-1 protease, feline immunodeficiency virus protease, and HIV-1 integrase are rationalized in terms of the dehydron distribution, revealing possible improvements in the targeting strategy. Principles of design optimization are proposed to create an inhibitor that can be neutralized only at the expense of the loss of catalytic function. The possibility of using drugs that wrap dehydrons to block protein–protein associations is also discussed

Technological inclusiveness: Northern versus Chinese induced technologies in the garment industry

The Northern economies have been the main sources of technologies for the global garment manufacturing industry. Over the past decade, China has become an important alternative source of these technologies offering a range of technological choices for small scale and dispersed production of cheap consumer goods, particularly in the developing world. Preceding a national foresight exercise aimed at enhancing the capabilities of small-scale garment producers in Uganda, we examine the potential ‘inclusiveness’ of garment sewing machines imported from the Northern economies and China, and their individual potential to enhance the capabilities of poor garment producers, particularly, women and rural dwellers. Data for our study included a survey and semi-structured interviews with 147 garment firms and other key informants. Compared to the Chinese sewing machines, we found that the Northern machines have high acquisition cost, relies on scale and advanced infrastructure, and tend to exclude poor rural producers (often women). The transfer of Chinese technologies to Uganda, we also found is much easier, have larger spread effects, leading to smaller gaps in technological know-how between China and Uganda because of the context in which Chinese technological innovations are induced. We conclude with some implication of our study to theory and policy