![]() ![]() ![]() The obtained proteins are very potent and highly specific inhibitors of HIV entry and provide a broad reactivity against genetically different virus strains. In the present study, we generated a panel of Designed Ankyrin Repeat Proteins that bind specifically to the cellular CD4 receptor, the main entry receptor of HIV. Using this technique, Designed Ankyrin Repeat Proteins can be evolved that bind their target molecules as specifically and efficiently as antibodies. To derive highly potent and specific inhibitors of HIV entry for potential use as microbicide, we employed the recently developed Designed Ankyrin Repeat Protein technology. The development of specific HIV inhibitors as microbicides, agents that by topical application prevent infection, is considered particularly important in limiting the spread of HIV in the absence of effective vaccines. There is an increasing need to develop inhibitors of HIV entry into target cells for both application in therapy and prevention. These novel CD4 targeting molecules described here combine the unique characteristics of DARPins-high physical stability, specificity and low production costs-with the capacity to potently block HIV entry, rendering them promising candidates for microbicide development. Importantly, the actions of the CD4 binding DARPins were highly specific: no effect on cell viability or activation, CD4 memory cell function, or interference with CD4-independent virus entry was observed. #Fischer Pool Table Serial Numbers seriesThese 2nd series DARPins potently inhibit infection of genetically divergent (subtype B and C) HIV isolates in the low nanomolar range, independent of coreceptor usage. In consequence, a second series of CD4-specific DARPins with improved affinity for CD4 was generated. DARPin proteins derived in the initial selection series inhibited HIV in a dose-dependent manner, but showed a relatively high variability in their capacity to block replication of patient isolates on primary CD4 T cells. Selected pool members interacted specifically with CD4 and competed with gp120 for binding to CD4. DARPin proteins specific for human CD4 were selected from a DARPin DNA library using ribosome display. ![]() Here, we describe the generation of a novel type of HIV entry inhibitor using the recently developed Designed Ankyrin Repeat Protein (DARPin) technology. ![]()
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