Offering the full range of contraceptive options: a survey of interest in vasectomy training in the US family planning community.

OBJECTIVE: To assess current practices regarding female and male sterilization counseling and provision, as well as determine interest in providing vasectomy among family planning specialists. METHODS: Members of the US-based network of family planning fellowship physicians (current fellows, graduates and faculty) received a Web-based survey from November 2015 through January 2016 regarding current sterilization preferences and practices, as well as interest in obtaining training in vasectomy counseling and procedure. RESULTS: Nearly 60% (n=178/302) of family planning fellowship providers responded to the survey. While 62% (111/178) of respondents reported counseling their patients about vasectomy at least most of the time and 57% (102/178) recommended vasectomy over female sterilization, few (8/178; 4 trained in family medicine and 4 trained in obstetrics and gynecology) had performed a vasectomy in the last year. Nearly 90% (158/178) of respondents were somewhat or very interested in receiving training on vasectomy counseling; 58% (103/178) desired procedural training. Desire for training was associated with being male and receiving residency training in family medicine. CONCLUSIONS: Few family planning fellowship physicians provide vasectomy, and the majority expressed being at least somewhat interested in receiving further training. IMPLICATIONS: Vasectomy is more effective, safer and less expensive than female sterilization but is less common than female sterilization. One barrier to vasectomy access is the low number of vasectomy providers. Creating a structured vasectomy training program through the family planning fellowship may help to increase the number of vasectomy providers.

Assessing helical protein interfaces for inhibitor design.

Structure-based design of synthetic inhibitors of protein-protein interactions (PPIs) requires adept molecular design and synthesis strategies as well as knowledge of targetable complexes. To address the significant gap between the elegant design of helix mimetics and their sporadic use in biology, we analyzed the full set of helical protein interfaces in the Protein Data Bank to obtain a snapshot of how helices that are critical for complex formation interact with the partner proteins. The results of this study are expected to guide the systematic design of synthetic inhibitors of PPIs. We have experimentally evaluated new classes of protein complexes that emerged from this data set, highlighting the significance of the results described herein.

Systematic analysis of helical protein interfaces reveals targets for synthetic inhibitors.

Synthetic inhibitors of protein-protein interactions are being discovered despite the inherent challenge in targeting large contact surfaces with small molecules. An analysis of available examples identifies common features of complexes that make them tractable for small molecules. We deduced that relative disposition and energetic contributions of "hot spot" residues provide a predictive scale for the potential of protein-protein interactions to be inhibited by small molecules. On the basis of this model, we analyzed the full set of helical protein interfaces in the Protein Data Bank to identify those that are potentially suitable candidates for synthetic ligands.

Evaluation of triazolamers as active site inhibitors of HIV-1 protease.

Proteases typically recognize their peptide substrates in extended conformations. General approaches for designing protease inhibitors often consist of peptidomimetics that feature this conformation. Herein we discuss a combination of computational and experimental studies to evaluate the potential of triazole-linked beta-strand mimetics as inhibitors of HIV-1 protease activity.

Assessment of helical interfaces in protein-protein interactions.

Herein we identify and analyze helical protein interfaces as potential targets for synthetic modulators of protein-protein interactions.

Contemporary strategies for the stabilization of peptides in the alpha-helical conformation.

Herein we review contemporary synthetic and protein design strategies to stabilize the alpha-helical motif in short peptides and miniature proteins. Advances in organometallic catalyst design, specifically for the olefin metathesis reaction, enable the use of hydrocarbon bridges to either crosslink side chains of specific residues or mimic intramolecular hydrogen bonds with carbon-carbon bonds. The resulting hydrocarbon-stapled and hydrogen bond surrogate alpha-helices provide unique synthetic ligands for targeting biomolecules. In the protein design realm, several classes of miniature proteins that display stable helical domains have been engineered and manipulated with powerful in vitro selection technologies to yield libraries of sequences that retain their helical folds. Rational re-design of these scaffolds provide distinctive reagents for the modulation of protein-protein interactions.

A hydrogen bond surrogate approach for stabilization of short peptide sequences in alpha-helical conformation.

Alpha-helices constitute the largest class of protein secondary structures and play a major role in mediating protein-protein interactions. Development of stable mimics of short alpha-helices would be invaluable for inhibition of protein-protein interactions. This Account describes our efforts in developing a general approach for constraining short peptides in alpha-helical conformations by a main-chain hydrogen bond surrogate (HBS) strategy. The HBS alpha-helices feature a carbon-carbon bond derived from a ring-closing metathesis reaction in place of an N-terminal intramolecular hydrogen bond between the peptide i and i + 4 residues. Our approach is centered on the helix-coil transition theory in peptides, which suggests that the energetically demanding organization of three consecutive amino acids into the helical orientation inherently limits the stability of short alpha-helices. The HBS method affords preorganized alpha-turns to overcome this intrinsic nucleation barrier and initiate helix formation. The HBS approach is an attractive strategy for generation of ligands for protein receptors because placement of the cross-link on the inside of the helix does not block solvent-exposed molecular recognition surfaces of the molecule. Our metathesis-based synthetic strategy utilizes standard Fmoc solid phase peptide synthesis methodology, resins, and reagents and provides HBS helices in sufficient amounts for subsequent biophysical and biological analyses. Extensive conformational analysis of HBS alpha-helices with 2D NMR, circular dichroism spectroscopies and X-ray crystallography confirms the alpha-helical structure in these compounds. The crystal structure indicates that all i and i + 4 C=O and NH hydrogen-bonding partners fall within distances and angles expected for a fully hydrogen-bonded alpha-helix. The backbone conformation of HBS alpha-helix in the crystal structure superimposes with an rms difference of 0.75 A onto the backbone conformation of a model alpha-helix. Significantly, the backbone torsion angles for the HBS helix residues fall within the range expected for a canonical alpha-helix. Thermal and chemical denaturation studies suggest that the HBS approach provides exceptionally stable alpha-helices from a variety of short sequences, which retain their helical conformation in aqueous buffers at exceptionally high temperatures. The high degree of thermal stability observed for HBS helices is consistent with the theoretical predictions for a nucleated helix. The HBS approach was devised to afford internally constrained helices so that the molecular recognition surface of the helix and its protein binding properties are not compromised by the constraining moiety. Notably, our preliminary studies illustrate that HBS helices can target their expected protein receptors with high affinity.