Recombinant proteins are important therapeutics due to potent, highly specific, and nontoxic actions in vivo. However, they are expensive medicines to manufacture, chemically unstable, and difficult to administer with low patient uptake and compliance. Small molecule drugs are cheaper and more bioavailable, but less target-specific in vivo and often have associated side effects. Here we combine some advantages of proteins and small molecules by taking short amino acid sequences that confer potency and selectivity to proteins, and fixing them as small constrained molecules that are chemically and structurally stable and easy to make. Proteins often use short α-helices of just 1-4 helical turns (4-15 amino acids) to interact with biological targets, but peptides this short usually have negligible α-helicity in water. Here we show that short peptides, corresponding to helical epitopes from viral, bacterial, or human proteins, can be strategically fixed in highly α-helical structures in water. These helix-constrained compounds have similar biological potencies as proteins that bear the same helical sequences. Examples are (i) a picomolar inhibitor of Respiratory Syncytial Virus F protein mediated fusion with host cells, (ii) a nanomolar inhibitor of RNA binding to the transporter protein HIV-Rev, (iii) a submicromolar inhibitor of Streptococcus pneumoniae growth induced by quorum sensing pheromone Competence Stimulating Peptide, and (iv) a picomolar agonist of the GPCR pain receptor opioid receptor like receptor ORL-1. This approach can be generally applicable to downsizing helical regions of proteins with broad applications to biology and medicine.helix | inhibitor | structure | mimetic | anti-infective P roteins are key functional components that define life, aging, disease, and death. Their uses in medicine, science, and industry are however limited by their complexity, high costs, chemical instability, and low bioavailability. Consequently, new chemical technology is needed to create simpler, smaller, cheaper, more stable, and bioavailable molecules that can execute or inhibit selected functions of proteins. If generic approaches could be developed to stabilize or recreate new molecular shapes that mimic structural components of proteins (e.g., helices, turns, strands, and combinations), the resulting molecules could potentially be extremely valuable for interrogating biological systems and for exploring prospective applications such as new pharmaceuticals, diagnostics, vaccines, and nanomaterials.Some proteins elicit biological function through a single short α-helical segment (usually 4-15 amino acids in 1-4 helical turns) that interacts with nucleic acids or proteins (1-3). However, short synthetic peptides of this length are usually not thermodynamically stable helices in water and adopt only random structures (4). Techniques developed as generalized strategies for stabilising or mimicking short peptide α-helices have been limited by lack of helical structure in water, by sequence or context dependent helici...

A 13-residue peptide sequence from a respiratory syncitial virus fusion protein was constrained in an alpha-helical conformation by fusing two back-to-back cyclic alpha-turn mimetics. The resulting peptide, Ac-(3-->7; 8-->12)-bicyclo-FP[KDEFD][KSIRD]V-NH(2), was highly alpha-helical in water by CD and NMR spectroscopy, correctly positioning crucial binding residues (F488, I491, V493) on one face of the helix and side chain-side chain linkers on a noninteracting face of the helix. This compound displayed potent activity in both a recombinant fusion assay and an RSV antiviral assay (IC(50) = 36 nM) and demonstrates for the first time that back-to-back modular alpha-helix mimetics can produce functional antagonists of important protein-protein interactions.

Background: Anterior cruciate ligament (ACL) injury is one of the most frequent orthopaedic injuries and reasons for time loss in sports and carries significant implications, including posttraumatic osteoarthritis (OA). Instability associated with ACL injury has been linked to the development of secondary meniscal tears (defined as tears that develop after the initial ACL injury). To date, no study has examined secondary meniscal tears after ACL injury and their effect on OA and arthroplasty risk. Purpose: To describe the rates and natural history of secondary meniscal tears after ACL injury and to determine the effect of meniscal tear treatment on the development of OA and conversion to total knee arthroplasty (TKA). Study Design: Cohort study; Level of evidence, 3. Methods: A geographic database of >500,000 patients was reviewed to identify patients with primary ACL injuries between January 1, 1990, and December 31, 2005. Information was collected with regard to ACL injury treatment, rates/characteristics of the secondary meniscal tears, and outcomes, including development of OA and conversion to TKA. Kaplan-Meier and adjusted multivariate survival analyses were performed to test for the effect of meniscal treatment on survivorship free of OA and TKA. Results: Of 1398 primary ACL injuries, the overall rate of secondary meniscal tears was 16%. Significantly lower rates of secondary meniscal tears were noted among patients undergoing acute ACL reconstruction within 6 months (7%) as compared with patients with delayed ACL reconstruction (33%, P < .01) and nonoperative ACL management (19%, P < .01). Of the 235 secondary meniscal tears identified (196 patients), 11.5% underwent repair, 73% partial meniscectomy, and 16% were treated nonoperatively. Tears were most often medial in location (77%) and complex in morphology (56% of medial tears, 54% of lateral tears). At the time of final follow-up, no patient undergoing repair of a secondary meniscal tear (0%) underwent TKA, as opposed to 10.9% undergoing meniscectomy and 6.1% receiving nonoperative treatment ( P = .28). Conclusion: Secondary meniscal tears after ACL injury are most common among patients undergoing delayed surgical or nonoperative treatment of their primary ACL injuries. Secondary tears often present as complex tears of the medial meniscus and result in high rates of partial meniscectomy.

Background:Lateral meniscus posterior root tears (LMPRTs), if left untreated, can cause devastating effects to the knee, with rapid articular cartilage degeneration and loss of the meniscus as a secondary stabilizer. Detection and surgical repair of these defects have been linked to favorable outcomes, but preoperative identification of LMPRTs continues to be challenging.Purpose:To determine the rate of LMPRTs diagnosed preoperatively on magnetic resonance imaging (MRI) in a consecutive series of arthroscopically confirmed LMPRTs.Study Design:Case series; Level of evidence, 4.Methods:A retrospective cohort of 45 consecutive patients with arthroscopically confirmed LMPRTs between 2010 and 2017 were included in this study. The preoperative MRI report for each patient was evaluated and compared with intraoperative findings. Each preoperative MRI study was then reviewed by 2 fellowship-trained musculoskeletal radiologists who worked in consensus.Results:A total of 45 patients (32 males, 13 females) with arthroscopically confirmed LMPRTs and a mean age of 27 years (range, 14-54 years) were included in the study. Only 15 of 45 LMPRTs (33%) were initially diagnosed on preoperative MRI. Past or concurrent anterior cruciate ligament (ACL) reconstruction was present in 37 of 45 cases (82%). Upon retrospective review, 15 of the 30 missed LMPRTs were “clearly evident,” 12 “subtly evident,” and 3 “occult” (unavoidably missed). There were no significant differences in the rate of LMPRT diagnosis based on history of prior knee surgery, meniscus extrusion, or tearing of the meniscofemoral ligament.Conclusion:Despite improved identification of other meniscus tear patterns on MRI, a high percentage of LMPRTs were still missed. In the setting of previous ACL reconstruction, if the root cannot be confidently identified, the MRI interpretation should indicate that “the root is poorly visualized” to alert the surgeon to thoroughly evaluate this structure. The surgeon should maintain a high index of suspicion and carefully probe the posterior root of the lateral meniscus at the time of arthroscopy, especially in cases of ACL injury.

Background:Surgical reconstruction of the anterior cruciate ligament (ACL) is one of the most common orthopaedic procedures, with an estimated 100,000 to 175,000 procedures performed annually. Recently, the all-inside reconstruction technique has come into favor and is theorized to be superior to the complete tibial tunnel technique.Purpose:To compare clinical and patient-reported outcomes (PROs) for hamstring autograft ACL reconstruction (ACLR) performed with an all-inside versus a complete tibial tunnel technique.Study Design:Cohort study; Level of evidence, 3.Methods:Patients who underwent hamstring autograft ACLR via either an all-inside approach (femoral and tibial sockets) or a complete tibial tunnel approach (femoral socket and full-length, transtibial tunnel) at a single institution between July 2011 and July 2015 were reviewed. Demographic information, preoperative comorbidities, surgical details, physical examination findings, and follow-up outcomes were extracted from the medical record. Physical examination data included pivot-shift, Lachman, and range of motion examinations, whereas PROs included the Tegner activity scale, Lysholm score, and International Knee Documentation Committee (IKDC) score at a minimum of 2 years after surgery. Return to sport and risk factors for failure were analyzed.Results:A total of 82 patients (mean ± SD age, 25.8 ± 10.2 years) who underwent all-inside reconstruction (median PRO follow-up, 30.1 months; range, 24.7-72.9 months) and 54 patients (mean ± SD age, 21.1 ± 7.3 years) who underwent complete tibial tunnel reconstruction (median PRO follow-up, 25.8 months; range, 23.9-74.5 months) met the inclusion criteria. PRO scores at latest follow-up were comparable between the all-inside versus the complete tibial tunnel groups (Lysholm score, 93.8 vs 94.4, P = .621; IKDC score, 93.5 vs 93.3, P = .497; Tegner activity score, 6.4 vs 6.8, P = .048). Complications (including graft failure) were experienced by 20% of patients in the all-inside group compared with 24% in the complete tibial tunnel group (P = .530). Graft failure before the final follow-up was experienced by 10% of patients in the all-inside group compared with 19% in the complete tibial tunnel group (P = .200). Mean return to sport was 12.5 months in the all-inside group versus 9.9 months in the complete tibial tunnel group (P = .028).Conclusion:All-inside and complete tibial tunnel hamstring autograft ACLR resulted in excellent physical examination findings and PROs at minimum 2-year follow-up. Both techniques successfully restored knee stability and patient function.

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Satisfactory clinical outcomes are achievable for radial meniscal tear repair at short-term follow-up. In a robustly matched comparison, radial and bucket-handle meniscal tears demonstrate similar improvements in VAS and IKDC scores, restoration of preoperative Tegner scores, and acceptable reoperation rates. Full-thickness radial meniscal tears should be considered for repair.

Background: Studies have shown good and excellent clinical and radiographic results after meniscal repair. Limited published information exists on the long-term outcomes, however, especially in a pediatric and adolescent population. Purpose: To determine long-term results of meniscal repair and concomitant anterior cruciate ligament (ACL) reconstruction in a pediatric and adolescent population. Specifically, the aims were to determine the clinical success rate of meniscal repair with concomitant ACL reconstruction, compare results with midterm outcomes, and analyze risk factors for failure. Study Design: Case series; Level of evidence, 4. Methods: Cases of meniscal repair with concomitant ACL reconstruction between 1990 and 2005 were reviewed among patients aged ≤18 years. Patient demographics, injury history, and surgical details were recorded, and risk factors for failure were analyzed. Physical examination findings and clinical outcomes at latest available follow-up were collected. Subjective knee outcomes were compared with midterm results. Descriptive statistics and univariate analysis were used to evaluate the available data. Results: Forty-seven patients (30 females, 17 males) with a mean age of 16 years (SD, 1.37) and a mean follow-up of 16.6 years (SD, 3.57) were included in this study. Overall, 13 patients (28%) failed meniscal repair and required repeat surgery at the time of final follow-up. Of the 13 failures, 9 underwent a subsequent meniscectomy; 2, meniscectomy and revision ACL reconstruction; 1, meniscal repair and revision ACL reconstruction; and 1, meniscal repair and subsequent meniscectomy. Mean International Knee Documentation Committee scores improved from 47.9 preoperatively to 87.7 postoperatively ( P < .01), and the mean score at long-term follow-up (87.7) did not significantly differ from that at the midterm follow-up (88.5) at a mean 7.4 years ( P = .97). Mean Tegner Activity Scale scores improved from 1.9 preoperatively to 6.3 postoperatively ( P < .01) and decreased from 8.3 at preinjury to 6.3 at final long-term follow-up ( P < .01). Conclusion: In conclusion, the long-term overall clinical success rate (failure-free survival) was 72% for repair of pediatric and adolescent meniscal tears in the setting of concomitant ACL reconstruction. Patients reported excellent knee subjective outcome scores that remained favorable when compared with midterm follow-up.